About the gene
No gene-level summary was recorded for this case.
Previous versions
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
VUS: no adjudicated criteria were met or applied, so the generic ACMG/AMP 2015 combination thresholds for pathogenic or benign classification were not satisfied.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
No screenshot for this evidence
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
No listed criterion applied
gnomAD-Canada ↗
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
No screenshot for this evidence
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
No screenshot for this evidence
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 0 met · 0 not met · 19 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
Under generic ACMG/AMP rules, PVS1 is not applicable because the submitted c.1100-3 substitution is outside the named canonical ±1/±2 splice-site and other null-variant classes; normalization and gene-level LOF context are unresolved.
PM4 and BP3 are not applicable because the submitted variant is an intronic single-nucleotide substitution, not an in-frame insertion/deletion or stop-loss variant.
All five requested criteria are not_assessed because the variant could not be normalized and the case evidence lacks the clinical, case-control, alternate-molecular-basis, and exact-variant ClinVar expert-panel data required for adjudication.
PP3 and BP4 are within scope only through the intronic SpliceAI path, but the variant could not be normalized and no SpliceAI score is available.
BP7 is outside scope because the submitted variant is intronic rather than synonymous.
All four population criteria are not assessed because the submitted intronic HGVS expression could not be normalized to a gene and genomic coordinate, leaving no usable population-frequency or healthy-adult observation data.
No criterion is inferred from another source's classification, and no VCEP-specific population rule applies because the case is governed by generic ACMG/AMP rules.
No criteria match.
Not assessed · 19 · no assessment recorded
PS2 ACMG_2015Not assessed: no documented proband, family-history status, or confirmed maternity and paternity is available to evaluate de novo occurrence. Details ▾Hide ▴
Reasoning
No case evidence documents a proband with the disease, absence of family history, or confirmed maternity and paternity. Therefore, the required de novo observation cannot be assessed.
Rule
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Evidence considered
- The available case materials contain no proband-level de novo observation or parental testing results.
- No source documents confirmed maternity, confirmed paternity, or absence of family history.
Still missing
- Proband diagnosis and phenotype are not documented.
- Family-history status is not documented.
- Parental testing and confirmation of both maternity and paternity are not documented.
PS3 ACMG_2015Not assessed: no validated in vitro or in vivo functional assay evidence was available, and the variant could not be normalized for targeted evidence retrieval. Details ▾Hide ▴
Reasoning
No validated in vitro or in vivo functional study, assay result, control set, or biological-relevance assessment was available for this variant. Targeted evidence retrieval was incomplete because the submitted intronic HGVS expression could not be normalized and no gene or genomic coordinates were resolved. Therefore, the available record does not support assessing PS3 as met or not_met.
Rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Evidence considered
- The available case evidence contains no functional-study records or publications for this variant.
- Variant normalization failed: the submitted NM_000546.6:c.1100-3C>T expression produced an exon-boundary warning and no resolved gene or genomic coordinates.
Still missing
- Resolve the variant to a valid transcript and genomic representation.
- Review validated functional assay evidence with appropriate controls and demonstrated biological relevance for the resolved variant.
PS4 ACMGNot assessed: no case-control odds ratio or relative risk, confidence interval, or affected-versus-control prevalence data are available. Details ▾Hide ▴
Reasoning
PS4 cannot be assessed because the case contains no affected-case/control counts, prevalence estimate, relative risk, odds ratio, or confidence interval. The submitted HGVS expression also could not be normalized, so no exact variant-level case-control search could be completed. The governing numeric rule requires an odds ratio or relative risk greater than 5.0 and a confidence interval that excludes 1.0, but no value is available for the required comparison.
Rule
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
Evidence considered
- No case-control study, prevalence estimate, relative risk, odds ratio, or confidence interval was present in the available case evidence.
- Normalization failed for NM_000546.6:c.1100-3C>T; no gene or genomic coordinates were resolved.
Still missing
- Validated variant normalization
- Affected-case and control counts or a reported relative risk/odds ratio with confidence interval
PM2 ACMGNot assessed: no applicable population observation is available to test the <=0.0001 PM2 threshold or establish absence from controls. Details ▾Hide ▴
Reasoning
PM2 cannot be assessed because no population allele-frequency observations are available for the submitted variant. Absence or extreme rarity in the applicable population source, including any required non-cancer or exome-only subset, cannot be established, so the generic PM2 threshold of <=0.0001 cannot be applied.
Rule
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
Evidence considered
- No gnomAD, ESP, 1000 Genomes, or ExAC population record was available for evaluation; the available normalization result reported unresolved gene and genomic coordinates.
- Generic PM2 calibration supplied for this interpretation: allele frequency <=0.0001.
Still missing
- Resolve NM_000546.6:c.1100-3C>T to a valid transcript and genomic representation.
- Obtain the applicable all-comers or governing non-cancer/exome-only population data, including allele count, allele number, and quality metrics.
PM3 ACMG_2015Not assessed: no affected-proband observation, pathogenic allele, or parent/offspring phase testing establishes a PM3-relevant variant in trans. Details ▾Hide ▴
Reasoning
PM3 cannot be assessed because the case provides no resolved gene or disease inheritance mode, no affected-proband observation, no pathogenic allele in trans, and no parent or offspring testing establishing phase. The submitted HGVS expression also failed normalization, leaving the allelic evidence unresolved.
Rule
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
Evidence considered
- The case evidence reports no resolved gene, disease context, inheritance mode, ClinVar result, or literature sources.
- The normalization record reports an ExonBoundaryError and LovdSyntaxcheckInvalid for NM_000546.6:c.1100-3C>T, with no genomic coordinates or transcript consequence resolved.
- No affected-proband observation, co-occurring pathogenic variant, or parent/offspring phase test is documented.
Still missing
- Resolve the submitted HGVS expression and identify the gene and associated disease.
- Establish whether the disorder is recessive and document an affected proband.
- Identify a pathogenic variant in the same individual and confirm it is in trans by parent or offspring testing.
PM6 ACMG_2015Not assessed: no proband de novo observation or parental testing status is documented for the variant. Details ▾Hide ▴
Reasoning
No case evidence documents an assumed de novo variant in the proband or parental testing status. The available materials therefore do not support assessment of PM6.
Rule
Assumed de novo, but without confirmation of paternity and maternity.
Evidence considered
- The available case materials contain no clinical report or family study documenting an assumed de novo occurrence.
- No parental testing results or statement that maternity and paternity were unconfirmed is available.
Still missing
- A proband-level de novo observation is not documented.
- Maternity and paternity testing status is not documented.
PP1 ACMG_2015Not assessed: no affected relatives, matching genotypes, phenotype data, or informative meioses are documented for segregation analysis. Details ▾Hide ▴
Reasoning
No affected relatives, family structure, genotype results, phenotype assessments, or meioses are documented. Co-segregation in multiple affected family members therefore cannot be assessed.
Rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Evidence considered
- The available case materials contain no pedigree, affected-relative testing, or segregation results.
- No family-level phenotype or genotype information is available to establish co-segregation.
Still missing
- Affected family members and their phenotypes are not documented.
- Genotypes for relatives are not documented.
- The number of informative meioses is not documented.
PP3 ACMG_2015Not assessed: the applicable intronic SpliceAI path has no score, and transcript validation could not confirm the c.1100-3 location. Details ▾Hide ▴
Reasoning
The variant is written at an intronic position (c.1100-3), so the applicable PP3 path is SpliceAI only; REVEL and other protein-impact predictors are not applicable. No SpliceAI score or max delta is available, and transcript normalization failed with an exon-boundary validation warning, so PP3 cannot be assessed.
Rule
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Evidence considered
- The case identifies NM_000546.6:c.1100-3C>T, but normalization did not resolve the gene or coordinates.
- VariantValidator reported that c.1100-3 does not correspond with an exon boundary for NM_000546.6 and that genomic context is required to verify the intronic position.
- No SpliceAI result or max-delta value is available.
Still missing
- Validated transcript consequence and exon-boundary context
- SpliceAI score or maximum delta for the normalized variant
PP4 ACMG_2015Not assessed: no patient phenotype or family history is provided to establish specificity for a single-gene disease. Details ▾Hide ▴
Reasoning
PP4 cannot be assessed because the case evidence contains no patient phenotype, family history, disease diagnosis, or disease-specific phenotype description. The governing rule requires a phenotype or family history highly specific for a disease with a single genetic etiology; that information is absent.
Rule
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Evidence considered
- The available case summary and evidence files contain no patient phenotype, family history, or disease-specific clinical description.
Still missing
- Patient phenotype and diagnostic features
- Family history and a defined disease with a single genetic etiology
PP5 ACMG_2015Not assessed: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available. Details ▾Hide ▴
Reasoning
PP5 cannot be assessed because exact-variant ClinVar expert-panel evidence is unavailable. ClinVar retrieval was skipped after variant normalization failed, and no expert-panel classification is present in the case evidence. Ordinary laboratory submissions, aggregate labels, or non-expert assertions would not satisfy the governing PP5 condition.
Rule
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
- ClinVar retrieval was skipped because normalization did not resolve the gene or coordinates.
- No exact-variant expert-panel assertion was present in the available evidence; no laboratory-only or aggregate classification was used.
Still missing
- Validated exact-variant normalization
- Exact-variant ClinVar expert-panel classification and review status
BA1 ACMGNot assessed: no population allele-frequency observation is available, so comparison with the >=0.05 BA1 threshold is impossible. Details ▾Hide ▴
Reasoning
BA1 cannot be assessed because no allele-frequency observations are available from ESP, 1000 Genomes, ExAC, gnomAD, or another population dataset for the submitted variant. Variant normalization failed, leaving the gene and genomic coordinates unresolved; therefore no comparison with the generic BA1 threshold of >=0.05 can be made.
Rule
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
Evidence considered
- No gnomAD, ESP, 1000 Genomes, or ExAC population record was available for evaluation; the available normalization result reported unresolved gene and genomic coordinates.
- Generic BA1 calibration supplied for this interpretation: allele frequency >=0.05.
Still missing
- Resolve NM_000546.6:c.1100-3C>T to a valid transcript and genomic representation.
- Obtain population allele counts, allele number, frequency, ancestry breakdown, and quality information from the applicable population datasets.
BS1 ACMG_2015Not assessed: no observed population frequency is available for comparison with the generic BS1 threshold of >=0.01. Details ▾Hide ▴
Reasoning
BS1 cannot be assessed because no population allele-frequency observations are available for the submitted variant and no disease prevalence, penetrance, or gene-specific maximum credible frequency can be established from the case data. Consequently, the generic BS1 threshold of >=0.01 cannot be compared with an observed frequency.
Rule
Allele frequency is greater than expected for disorder.
Evidence considered
- No gnomAD, ESP, 1000 Genomes, or ExAC population record was available for evaluation; the available normalization result reported unresolved gene and genomic coordinates.
- Generic BS1 calibration supplied for this interpretation: allele frequency >=0.01.
Still missing
- Resolve the variant to a valid genomic representation.
- Obtain population frequency data and establish the disorder's prevalence, penetrance, and appropriate maximum credible allele frequency.
BS2 ACMG_2015Not assessed: no healthy-adult homozygote, heterozygote, or hemizygote observation is available and penetrance is unresolved. Details ▾Hide ▴
Reasoning
BS2 cannot be assessed because no observation of the submitted variant in a healthy adult is available, and the case does not establish the relevant inheritance model or that full penetrance is expected at an early age. No homozygote, heterozygote, or hemizygote evidence is therefore available.
Rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Evidence considered
- No healthy-adult carrier, homozygote, or hemizygote observation was available in the supplied evidence.
- The gene, disorder, inheritance model, and penetrance context were unresolved in the available case data.
Still missing
- Resolve the variant and identify any reliable healthy-adult observations.
- Establish the disorder's inheritance model and whether full early-age penetrance is expected.
BS3 ACMG_2015Not assessed: no validated in vitro or in vivo functional assay evidence was available, and the variant could not be normalized for targeted evidence retrieval. Details ▾Hide ▴
Reasoning
No validated in vitro or in vivo functional study, assay result, control set, or biological-relevance assessment was available for this variant. Targeted evidence retrieval was incomplete because the submitted intronic HGVS expression could not be normalized and no gene or genomic coordinates were resolved. Therefore, the available record does not support assessing BS3 as met or not_met.
Rule
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Evidence considered
- The available case evidence contains no functional-study records or publications for this variant.
- Variant normalization failed: the submitted NM_000546.6:c.1100-3C>T expression produced an exon-boundary warning and no resolved gene or genomic coordinates.
Still missing
- Resolve the variant to a valid transcript and genomic representation.
- Review validated functional assay evidence showing no damaging effect on protein function or splicing, with appropriate controls and biological relevance.
BS4 ACMG_2015Not assessed: no affected relatives with documented variant status and phenotype are available to evaluate lack of segregation. Details ▾Hide ▴
Reasoning
No affected family members, their variant status, or phenotype information is documented. Lack of segregation and the phenocopy or multiple-pathogenic-variant caveats therefore cannot be evaluated.
Rule
Lack of segregation in affected members of a family.
Evidence considered
- The available case materials contain no non-segregation observation in affected family members.
- No family data are available to assess phenocopies or the possibility of more than one pathogenic variant.
Still missing
- Affected relatives and their clinical phenotypes are not documented.
- Variant testing results for affected relatives are not documented.
- Potential phenocopies or additional pathogenic variants cannot be evaluated.
BP2 ACMG_2015Not assessed: no resolved inheritance mode or documented cis/trans relationship with a pathogenic variant is available for BP2. Details ▾Hide ▴
Reasoning
BP2 cannot be assessed because the case provides no resolved gene or inheritance mode and no observation establishing either trans occurrence with a pathogenic variant in a fully penetrant dominant disorder or cis occurrence with a pathogenic variant. The submitted HGVS expression failed normalization, so the relevant allelic context is unresolved.
Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
- The case evidence reports no resolved gene, disease context, inheritance mode, ClinVar result, or literature sources.
- The normalization record reports an ExonBoundaryError and LovdSyntaxcheckInvalid for NM_000546.6:c.1100-3C>T, with no genomic coordinates or transcript consequence resolved.
- No pathogenic allele or cis/trans phase observation is documented.
Still missing
- Resolve the submitted HGVS expression and identify the gene and associated disease.
- Establish whether the dominant disorder is fully penetrant, if evaluating the trans pathway.
- Document the pathogenic variant and confirm whether the variants are in trans or cis.
BP4 ACMG_2015Not assessed: the applicable intronic SpliceAI path has no score, and transcript validation could not confirm the c.1100-3 location. Details ▾Hide ▴
Reasoning
The variant is written at an intronic position (c.1100-3), so the applicable BP4 path is SpliceAI only; REVEL and other protein-impact predictors are not applicable. No SpliceAI score or max delta is available, and transcript normalization failed with an exon-boundary validation warning, so BP4 cannot be assessed.
Rule
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Evidence considered
- The case identifies NM_000546.6:c.1100-3C>T, but normalization did not resolve the gene or coordinates.
- VariantValidator reported that c.1100-3 does not correspond with an exon boundary for NM_000546.6 and that genomic context is required to verify the intronic position.
- No SpliceAI result or max-delta value is available.
Still missing
- Validated transcript consequence and exon-boundary context
- SpliceAI score or maximum delta for the normalized variant
BP5 ACMG_2015Not assessed: no alternate molecular basis for the disease is documented in the available case evidence. Details ▾Hide ▴
Reasoning
BP5 cannot be assessed because no case evidence documents an alternate molecular basis for the disease. The available files contain no independent pathogenic molecular diagnosis or other alternate molecular cause to support the criterion.
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
- No alternate pathogenic molecular diagnosis or other alternate molecular basis was documented in the available case evidence.
Still missing
- Confirmed disease phenotype or diagnosis
- Independent alternate molecular cause documented in the same case
BP6 ACMG_2015Not assessed: no exact-variant ClinVar expert-panel Benign or Likely benign classification is available. Details ▾Hide ▴
Reasoning
BP6 cannot be assessed because exact-variant ClinVar expert-panel evidence is unavailable. ClinVar retrieval was skipped after variant normalization failed, and no expert-panel classification is present in the case evidence. Ordinary laboratory submissions, aggregate labels, or non-expert assertions would not satisfy the governing BP6 condition.
Rule
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
- ClinVar retrieval was skipped because normalization did not resolve the gene or coordinates.
- No exact-variant expert-panel assertion was present in the available evidence; no laboratory-only or aggregate classification was used.
Still missing
- Validated exact-variant normalization
- Exact-variant ClinVar expert-panel classification and review status
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: the submitted intronic substitution is at position -3, outside PVS1's named canonical ±1 or ±2 splice-site locations and other null-variant classes. Details ▾Hide ▴
Reasoning
The submitted HGVS expression NM_000546.6:c.1100-3C>T describes an intronic substitution at position -3, outside the PVS1 rule's named canonical +1, +2, -1, or -2 splice-site locations and outside the other named null-variant classes (nonsense, frameshift, initiation-codon, or single/multi-exon deletion). The case cannot establish a transcript consequence, NMD effect, exon importance, or gene-level loss-of-function mechanism because normalization failed and gene/transcript consequence fields remain unresolved; those unresolved facts do not convert this variant into a PVS1-eligible variant class.
Rule
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Evidence considered
- The submitted variant is NM_000546.6:c.1100-3C>T, an intronic -3 substitution by its stated HGVS position; it is not a nonsense, frameshift, initiation-codon, or exon-deletion variant.
- VariantValidator reported ExonBoundaryError for c.1100-3 and did not provide a normalized transcript consequence, gene symbol, protein consequence, or exon assignment.
- The case's gene-level PVS1 context is unresolved and does not establish a loss-of-function disease mechanism.
Still missing
- Normalization and transcript consequence remain unresolved; the submitted HGVS expression was flagged as not syntactically correct and not an exon boundary by VariantValidator.
- Gene-level loss-of-function disease mechanism, NMD sensitivity, and exon importance cannot be evaluated from the unresolved case data.
PS1 N/ANot applicable: c.1100-3C>T is intronic with no resolved amino acid change, so the same-amino-acid comparison required for PS1 cannot apply. Details ▾Hide ▴
Reasoning
PS1 is not applicable because the submitted variant is NM_000546.6:c.1100-3C>T, an intronic variant at c.-3 with no resolved protein consequence; therefore it is outside the rule's required comparison of the same amino acid change as a previously established pathogenic variant.
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Evidence considered
- VariantValidator identified NM_000546.6:c.1100-3C>T as an intronic submission and reported no predicted protein consequence; normalization did not resolve a gene, coding consequence, or protein change.
PM1 N/ANot applicable: c.1100-3C>T has no resolved protein residue, so hotspot or critical-domain placement cannot be evaluated for this missense criterion. Details ▾Hide ▴
Reasoning
PM1 is not applicable because the submitted variant is intronic at c.1100-3 and has no resolved protein residue; the rule concerns location in a mutational hotspot or critical functional domain, which requires a protein-level location for this missense context.
Rule
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Evidence considered
- VariantValidator reported NM_000546.6:c.1100-3C>T as intronic with no predicted protein consequence, and the case normalization did not resolve a protein residue or gene.
PM4 N/ANot applicable: the submitted variant is an intronic single-nucleotide substitution, not an in-frame insertion/deletion or stop-loss variant causing a protein-length change. Details ▾Hide ▴
Reasoning
PM4 is limited to protein length changes caused by in-frame deletions or insertions in a non-repeat region or by stop-loss variants. The submitted variant is an intronic single-nucleotide substitution at c.1100-3, not an in-frame insertion, in-frame deletion, or stop-loss variant; therefore the PM4 variant-type gate is not met.
Rule
PM4: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- The submitted HGVS expression NM_000546.6:c.1100-3C>T describes a single-nucleotide substitution at an intronic position, not an in-frame insertion or deletion.
- No stop-loss or protein-length change is identified; transcript normalization failed, but the stated variant type is outside PM4's named variant classes.
PM5 N/ANot applicable: c.1100-3C>T is intronic with no resolved amino acid residue, so an alternate pathogenic missense change at the same residue cannot be assessed. Details ▾Hide ▴
Reasoning
PM5 is not applicable because the submitted variant is intronic at c.1100-3 and has no resolved amino acid residue; therefore it cannot be evaluated as a novel missense change at a residue with a previously pathogenic alternate missense change.
Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Evidence considered
- VariantValidator classified the submitted change as intronic and supplied no predicted protein consequence; normalization did not produce a protein-level variant.
PP2 N/ANot applicable: c.1100-3C>T is intronic, not a missense variant, and has no resolved gene-level missense mechanism for PP2. Details ▾Hide ▴
Reasoning
PP2 is not applicable because the submitted variant is intronic rather than a missense variant; no protein consequence or gene-level missense mechanism was resolved for this case.
Rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
- The submitted HGVS change is intronic at c.1100-3, and normalization failed to resolve the gene, coding consequence, or protein change.
BP1 N/ANot applicable: c.1100-3C>T is intronic, not missense, and the gene was not resolved for evaluating a primarily truncating disease mechanism. Details ▾Hide ▴
Reasoning
BP1 is not applicable because the submitted variant is intronic rather than a missense variant; the case also lacks a resolved gene for assessing whether disease is primarily caused by truncating variants.
Rule
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Evidence considered
- The submitted HGVS change is intronic at c.1100-3; normalization failed to resolve the gene, coding consequence, or protein change.
BP3 N/ANot applicable: the submitted intronic single-nucleotide substitution is not an in-frame insertion or deletion, the required BP3 variant type. Details ▾Hide ▴
Reasoning
BP3 is limited to in-frame deletions or insertions in a repetitive region without a known function. The submitted variant is an intronic single-nucleotide substitution at c.1100-3, not an in-frame insertion or deletion, so BP3 is outside its governing variant-type applicability regardless of repeat-region context.
Rule
BP3: In frame-deletions/insertions in a repetitive region without a known function.
Evidence considered
- The submitted HGVS expression NM_000546.6:c.1100-3C>T describes a single-nucleotide substitution at an intronic position, not an in-frame insertion or deletion.
- Because the required in-frame indel variant type is absent, repeat-region context and known function are not determinative for BP3.
BP7 N/ANot applicable: c.1100-3C>T is an intronic-position change, whereas BP7 applies only to synonymous variants. Details ▾Hide ▴
Reasoning
BP7 is restricted to synonymous variants. This variant is written as an intronic change at c.1100-3, not as a synonymous coding variant, so BP7 is outside its governing scope.
Rule
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
- The submitted HGVS expression uses the intronic position c.1100-3 rather than a synonymous coding position.
Identifiers
- Coding (HGVS c.)
- NM_000546.6:c.1100-3C>T
- Location and type
- unknown
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
No population statements were recorded.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ACMG_2015Not assessed: the applicable intronic SpliceAI path has no score, and transcript validation could not confirm the c.1100-3 location. Details ▾Hide ▴
Reasoning
The variant is written at an intronic position (c.1100-3), so the applicable PP3 path is SpliceAI only; REVEL and other protein-impact predictors are not applicable. No SpliceAI score or max delta is available, and transcript normalization failed with an exon-boundary validation warning, so PP3 cannot be assessed.
Rule
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Evidence considered
- The case identifies NM_000546.6:c.1100-3C>T, but normalization did not resolve the gene or coordinates.
- VariantValidator reported that c.1100-3 does not correspond with an exon boundary for NM_000546.6 and that genomic context is required to verify the intronic position.
- No SpliceAI result or max-delta value is available.
Still missing
- Validated transcript consequence and exon-boundary context
- SpliceAI score or maximum delta for the normalized variant
BP4 ACMG_2015Not assessed: the applicable intronic SpliceAI path has no score, and transcript validation could not confirm the c.1100-3 location. Details ▾Hide ▴
Reasoning
The variant is written at an intronic position (c.1100-3), so the applicable BP4 path is SpliceAI only; REVEL and other protein-impact predictors are not applicable. No SpliceAI score or max delta is available, and transcript normalization failed with an exon-boundary validation warning, so BP4 cannot be assessed.
Rule
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Evidence considered
- The case identifies NM_000546.6:c.1100-3C>T, but normalization did not resolve the gene or coordinates.
- VariantValidator reported that c.1100-3 does not correspond with an exon boundary for NM_000546.6 and that genomic context is required to verify the intronic position.
- No SpliceAI result or max-delta value is available.
Still missing
- Validated transcript consequence and exon-boundary context
- SpliceAI score or maximum delta for the normalized variant
BP7 N/ANot applicable: c.1100-3C>T is an intronic-position change, whereas BP7 applies only to synonymous variants. Details ▾Hide ▴
Reasoning
BP7 is restricted to synonymous variants. This variant is written as an intronic change at c.1100-3, not as a synonymous coding variant, so BP7 is outside its governing scope.
Rule
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
- The submitted HGVS expression uses the intronic position c.1100-3 rather than a synonymous coding position.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.