About LZTR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
LZTR1 c.2219+13C>T, p.?
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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 ClinGen LZTR1 VCEP v1.3.0. 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: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
Population frequency is above the LZTR1 BA1 threshold. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both above the BA1 threshold of 0.05%, supporting a benign population frequency.
BS1Strong
BS1 · strong
Population frequency is above the LZTR1 BS1 threshold. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both above the BS1 threshold of 0.025%, supporting a benign population frequency.
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splice impact for this noncanonical intronic variant (max delta score 0.13), which supports a negligible predicted splicing effect and meets the LZTR1 BP4 computational rule for splicing variants.
BP7Supporting
BP7 · supporting
This variant is at a noncanonical intronic position (+13), and SpliceAI predicts no significant splice impact (max delta score 0.13). Under the LZTR1 specification, BP7 may be applied with BP4 for intronic variants outside the canonical splice site when computational evidence supports no splice effect.
Recorded classification: Benign
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.3.0 v1.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BP4 supporting, BS1 strong, BA1 stand-alone benign, BP7 supporting; maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
20,042 / 1,610,034 alleles
gnomAD v4.1: 20,042 / 1,610,034 alleles. Recorded AF 0.0124482. Recorded homozygote count 145.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0100413; MAF= 1.00413%, 2808/279646 alleles, homozygotes = 21) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0142263; MAF= 1.42263%, 1819/127862 alleles, homozygotes = 13); grpmax FAF= 0.0137781.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen LZTR1 VCEP v1.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 4 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The LZTR1 c.2219+13C>T (p.?) variant has been reported in ClinVar predominantly as benign, with 8 benign and 1 likely benign clinical laboratory submissions.
This variant is common in population databases, with gnomAD v2.1 grpmax filtering allele frequency 1.37781% and gnomAD v4.1 grpmax filtering allele frequency 1.43127%, both well above the LZTR1 benign thresholds for BS1 (0.025%) and BA1 (0.05%).
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.13, which is consistent with BP4 and BP7 rather than a deleterious splicing effect.
No criteria match.
Met · 4
BA1 Stand alonePopulation frequency is above the LZTR1 BA1 threshold. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both above the BA1 threshold of 0.05%, supporting a benign population frequency. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0137781
- gnomAD v4.1 grpmax FAF 0.0143127
- BA1 threshold 0.05%
Sources
BS1 StrongPopulation frequency is above the LZTR1 BS1 threshold. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both above the BS1 threshold of 0.025%, supporting a benign population frequency. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0137781
- gnomAD v4.1 grpmax FAF 0.0143127
- BS1 threshold 0.025%
Sources
BP4 SupportingSpliceAI predicts no significant splice impact for this noncanonical intronic variant (max delta score 0.13), which supports a negligible predicted splicing effect and meets the LZTR1 BP4 computational rule for splicing variants. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.13
- LZTR1 BP4 rule for splicing variants with negligible predicted effect
Sources
BP7 SupportingThis variant is at a noncanonical intronic position (+13), and SpliceAI predicts no significant splice impact (max delta score 0.13). Under the LZTR1 specification, BP7 may be applied with BP4 for intronic variants outside the canonical splice site when computational evidence supports no splice effect. Details ▾Hide ▴
Rule
Applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4 when splicing prediction algorithms predict no impact.
Evidence considered
- Intronic position c.2219+13
- SpliceAI max delta score 0.13
- LZTR1 BP7 rule for intronic noncanonical variants used with BP4
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This variant is intronic at c.2219+13 and is not a canonical ±1,2 splice-site, nonsense, or frameshift variant. The variant-level PVS1 assessment therefore does not place it in a default loss-of-function PVS1 category, so PVS1 is not met. Details ▾Hide ▴
Rule
Null variant in a gene where loss of function is a known mechanism of disease.
Evidence considered
- LZTR1 allows PVS1 for AR disease only
- PVS1 gene gate eligible
- Variant is noncanonical intronic and outside default generic PVS1 buckets
Sources
PS4 Available evidence does not show enrichment in affected individuals sufficient for the LZTR1 PS4 point thresholds (≥1 point for supporting), and the variant is common in population databases, which argues against a pathogenic case excess. Details ▾Hide ▴
Rule
Supporting at ≥1 point; Moderate at ≥3 points; Strong at ≥5 points.
Evidence considered
- No PS4 point-based case evidence identified
- High population frequency in gnomAD
- ClinVar submissions are predominantly benign/likely benign
Still missing
- RASopathy case-level point data meeting PS4 thresholds
Sources
PM2 Population frequency is not below the LZTR1 PM2 supporting threshold for autosomal recessive disease. The gnomAD v2.1 grpmax filtering allele frequency is 1.37781% and the gnomAD v4.1 grpmax filtering allele frequency is 1.43127%, both far above the PM2 threshold of 0.0025%, so PM2 is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD). For variants in LZTR1, PM2_P ≤0.0025% may be applied to support AR disease.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0137781
- gnomAD v4.1 grpmax FAF 0.0143127
- PM2_P threshold 0.0025%
Sources
PP3 Available in silico evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.13, so the predicted outcome does not support PP3. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.13
- No REVEL result because variant is non-missense
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo observations were identified, so PS2 cannot be scored. Details ▾Hide ▴
Rule
Moderate at 1 point; Strong at 2 points; Very Strong at 4 points.
Evidence considered
- No PS2 point-based case evidence identified
Still missing
- Case-level confirmed de novo data with maternity and paternity confirmation
Sources
PS3 No approved LZTR1 functional study results specific to this variant were identified, so PS3 cannot be applied. Details ▾Hide ▴
Rule
Supporting with one approved assay; Moderate with two or more different approved assays.
Evidence considered
- Approved LZTR1 assays exist
- but no variant-specific data were identified
Still missing
- Variant-specific approved functional assay data
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM3 No observations in trans with a pathogenic variant were identified, so PM3 cannot be evaluated for autosomal recessive disease. Details ▾Hide ▴
Rule
Supporting at ≥0.5 points; Moderate at ≥1 point; Strong at ≥2 points; Very Strong at ≥4 points.
Evidence considered
- No PM3 point-based case evidence identified
Still missing
- Case-level phase data showing trans occurrence with a pathogenic variant
Sources
cspec ↗vcep_lztr1_classification_flowchart_page_1
PM6 No assumed de novo observations were identified, so PM6 cannot be scored. Details ▾Hide ▴
Rule
Supporting at 0.5 points; Moderate at 1 point; Strong at 2 points.
Evidence considered
- No PM6 point-based case data identified
Still missing
- Case-level de novo data without confirmed maternity and paternity
Sources
PP1 No segregation data were identified, so co-segregation with disease cannot be evaluated. Details ▾Hide ▴
Rule
Supporting at ≥3 informative meioses; Moderate at ≥5; Strong at ≥7.
Evidence considered
- No informative meioses reported
Still missing
- Family segregation data
Sources
BS2 Although this variant is seen in homozygous state in gnomAD (21 homozygotes in v2.1 and 145 homozygotes in v4.1), unaffected clinical status and phenotype-specific evidence required for BS2 were not available, so BS2 was not independently applied. Details ▾Hide ▴
Rule
Supporting at -1 point; Strong at -4 points.
Evidence considered
- gnomAD v2.1 homozygotes 21
- gnomAD v4.1 homozygotes 145
- No phenotype curation for BS2 point scoring
Still missing
- Phenotyped unaffected carriers meeting BS2 point-based requirements
Sources
BS4 No non-segregation data were identified, so lack of segregation in affected relatives cannot be evaluated. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- No informative non-segregation data reported
Still missing
- Family non-segregation data
Sources
BP2 No case-level data were identified showing this variant with an alternate molecular explanation in the same gene or in cis/trans with a pathogenic variant, so BP2 cannot be evaluated. Details ▾Hide ▴
Rule
Supporting at ≥(-1) point; Moderate at ≥(-2) points; Strong at ≥(-4) points.
Evidence considered
- No BP2 point-based case evidence identified
Still missing
- Case-level phase data and alternate molecular cause information
Sources
BP5 No case-level data were identified showing an alternate molecular cause of disease in a different gene, so BP5 cannot be evaluated. Details ▾Hide ▴
Rule
Supporting at ≥(-1) point; Moderate at ≥(-2) points; Strong at ≥(-4) points.
Evidence considered
- No BP5 point-based case evidence identified
Still missing
- Case-level alternate molecular diagnosis data
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant does not define a known amino acid substitution, so PS1 cannot be applied. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- Protein consequence is p.?
- Variant is intronic rather than coding
Sources
PM1 N/APM1 is not used in this LZTR1 specification. Details ▾Hide ▴
PM4 N/AThis intronic variant does not change protein length and is not an in-frame insertion, in-frame deletion, or stop-loss variant. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is intronic
- Protein consequence is p.?
Sources
PM5 N/AThis variant does not create an amino acid substitution, so same-codon pathogenic missense comparisons cannot be applied. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon for Moderate; ≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands for Strong.
Evidence considered
- Protein consequence is p.?
- Variant is intronic rather than missense
Sources
PP2 N/APP2 is not used in this LZTR1 specification. Details ▾Hide ▴
PP4 N/APP4 is not used in this LZTR1 specification because the phenotype is genetically heterogeneous. Details ▾Hide ▴
PP5 N/APP5 is not used in this LZTR1 specification. Details ▾Hide ▴
BS3 N/ABS3 is not used in this LZTR1 specification. Details ▾Hide ▴
BP1 N/ABP1 is not used in this LZTR1 specification. Details ▾Hide ▴
BP3 N/ABP3 is not used in this LZTR1 specification. Details ▾Hide ▴
BP6 N/ABP6 is not used in this LZTR1 specification. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- LZTR1 specification marks BP6 as not applicable
Sources
Identifiers
- Gene
- LZTR1
- Transcript
- NM_006767.4
- Coding (HGVS c.)
- NM_006767.4:c.2219+13C>T
- Protein (HGVS p.)
- NP_006758.2:p.?
- GRCh38
- chr22:20996125 C>T
- GRCh37
- chr22:21350414 C>T
Gene diagram
Every interpreted variant in LZTR1, mapped onto the exon structure of NM_006767.4. Select a row to find it on the plot.
LZTR1NM_006767.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in LZTR1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
20,042 / 1,610,034 alleles
AF 0.0124 · 145 homozygotes · FAF 0.0143
gnomAD v2.1
2,808 / 279,646 alleles
AF 0.01 · 21 homozygotes · FAF 0.0138
By genetic ancestry
gnomAD v4.1
AF 0.012 · 20042 / 1,610,034 alleles · 145 hom · FAF 0.014
| European (non-Finnish)17089 / 1,178,968 | 0.014127 hom |
| Middle Eastern71 / 5,662 | 0.013 |
| Admixed American732 / 59,982 | 0.0126 hom |
| Remaining individuals747 / 62,390 | 0.0122 hom |
| European (Finnish)447 / 61,666 | 0.00723 hom |
| South Asian641 / 91,026 | 0.0076 hom |
| African/African American281 / 75,024 | 0.00371 hom |
| Ashkenazi Jewish30 / 29,546 | 0.001 |
| East Asian4 / 44,858 | 8.9e-05 |
0 alternate alleles recorded in 1 other group: Amish.
gnomAD v2.1
AF 0.01 · 2808 / 279,646 alleles · 21 hom · FAF 0.014
| European (non-Finnish)1819 / 127,862 | 0.01413 hom |
| Admixed American422 / 35,350 | 0.0125 hom |
| Remaining individuals84 / 7,174 | 0.012 |
| European (Finnish)189 / 23,624 | 0.0082 hom |
| South Asian193 / 30,572 | 0.00631 hom |
| African/African American85 / 24,882 | 0.0034 |
| Ashkenazi Jewish15 / 10,260 | 0.0015 |
| East Asian1 / 19,922 | 5e-05 |
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0124482; MAF= 1.24482%, 20042/1610034 alleles, homozygotes = 145) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0144949; MAF= 1.44949%, 17089/1178968 alleles, homozygotes = 127); grpmax FAF= 0.0143127.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0100413; MAF= 1.00413%, 2808/279646 alleles, homozygotes = 21) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0142263; MAF= 1.42263%, 1819/127862 alleles, homozygotes = 13); grpmax FAF= 0.0137781.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no significant splice impact for this noncanonical intronic variant (max delta score 0.13), which supports a negligible predicted splicing effect and meets the LZTR1 BP4 computational rule for splicing variants. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.13
- LZTR1 BP4 rule for splicing variants with negligible predicted effect
Sources
BP7 SupportingThis variant is at a noncanonical intronic position (+13), and SpliceAI predicts no significant splice impact (max delta score 0.13). Under the LZTR1 specification, BP7 may be applied with BP4 for intronic variants outside the canonical splice site when computational evidence supports no splice effect. Details ▾Hide ▴
Rule
Applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4 when splicing prediction algorithms predict no impact.
Evidence considered
- Intronic position c.2219+13
- SpliceAI max delta score 0.13
- LZTR1 BP7 rule for intronic noncanonical variants used with BP4
Sources
PP3 Available in silico evidence does not support a deleterious splicing effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.13, so the predicted outcome does not support PP3. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.13
- No REVEL result because variant is non-missense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
20,042 / 1,610,034 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1532496138
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/516329/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-21350414-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-20996125-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006767.4%3Ac.2219…
- OncoKB ↗www.oncokb.org/gene/LZTR1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105074710
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.0124482; MAF= 1.24482%, 20042/1610034 alleles, homozygotes = 145) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0144949; MAF= 1.44949%, 17089/1178968 alleles, homozygotes = 127); grpmax FAF= 0.0143127.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.0100413; MAF= 1.00413%, 2808/279646 alleles, homozygotes = 21) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0142263; MAF= 1.42263%, 1819/127862 alleles, homozygotes = 13); grpmax FAF= 0.0137781.
ClinVar
This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV104394247, n = 4 times).