About SPG11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SPG11 c.6062G>A, p.(Arg2021Gln)
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 Not recorded. 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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is rare in population databases. In gnomAD v2.1, the highest observed population frequency was 0.09023% in East Asian individuals, and in gnomAD v4.1 it was 0.05125% in East Asian individuals; both are below the 0.1% PM2 threshold used for this generic non-VCEP review.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational results support a benign interpretation. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, which together argue against a damaging protein or splice effect.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
76 / 1,614,168 alleles
gnomAD v4.1: 76 / 1,614,168 alleles. Recorded AF 4.70831e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.84242e-05; MAF= 0.00884%, 25/282728 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000902346; MAF= 0.09023%, 18/19948 alleles, homozygotes = 0); grpmax FAF= 0.00058897.
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 ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 14 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The SPG11 c.6062G>A (p.Arg2021Gln) variant has been reported in ClinVar with one likely benign submission and one uncertain significance submission.
This variant is rare in population databases, with the highest observed frequency in East Asian individuals of 0.09023% in gnomAD v2.1 and 0.05125% in gnomAD v4.1, both below the 0.1% PM2 threshold used for this generic non-VCEP review.
Computational data argue against a damaging effect, with REVEL 0.113, BayesDel -0.445237, and SpliceAI showing no significant predicted splice impact with a maximum delta score of 0.02.
No criteria match.
Met · 2
PM2 ModerateThis variant is rare in population databases. In gnomAD v2.1, the highest observed population frequency was 0.09023% in East Asian individuals, and in gnomAD v4.1 it was 0.05125% in East Asian individuals; both are below the 0.1% PM2 threshold used for this generic non-VCEP review. Details ▾Hide ▴
Rule
PM2 was applied because the highest observed population frequency remained below the 0.1% rarity threshold for this generic non-VCEP assessment.
Evidence considered
- gnomAD v2.1 East Asian AF 0.000902346 (18/19948)
- gnomAD v4.1 East Asian AF 0.000512501 (23/44878)
- Both below 0.001
Sources
BP4 SupportingMultiple computational results support a benign interpretation. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, which together argue against a damaging protein or splice effect. Details ▾Hide ▴
Rule
BP4 was applied because multiple computational predictors support no impact on the gene or gene product.
Evidence considered
- REVEL 0.113 supports a benign missense interpretation
- BayesDel -0.445237 supports a benign interpretation
- SpliceAI max delta 0.02 argues against splice disruption
Sources
Not met · 6 · evaluated, threshold not reached
PS4 Available evidence does not show enrichment of this variant in affected individuals compared with controls. The variant has limited ClinVar submissions and no case-control or prevalence data sufficient for PS4 were identified. Details ▾Hide ▴
Rule
PS4 requires increased prevalence in affected individuals over controls.
Evidence considered
- ClinVar has 1 likely benign and 1 uncertain significance submission
Still missing
- Need multiple independent affected observations or case-control enrichment data.
Sources
PM1 This variant has not been shown to lie in a well-established critical functional domain or statistically significant mutational hotspot. Cancer Hotspots did not identify a hotspot at residue Arg2021. Details ▾Hide ▴
Rule
PM1 requires location in a mutational hotspot or critical functional domain without benign variation.
Evidence considered
- No hotspot row identified for SPG11 Arg2021
Still missing
- Need validated domain-specific or clustering evidence for this residue or region.
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, so PP3 was not met. Details ▾Hide ▴
Rule
PP3 requires multiple computational predictors supporting a deleterious effect on the gene or gene product.
Evidence considered
- REVEL 0.113
- BayesDel -0.445237
- SpliceAI max delta 0.02
Sources
BA1 The population frequency is well below the 1% BA1 threshold. The highest observed population frequency was 0.09023% in gnomAD v2.1 East Asian individuals and 0.05125% in gnomAD v4.1 East Asian individuals. Details ▾Hide ▴
Rule
BA1 requires allele frequency above the stand-alone benign threshold.
Evidence considered
- Highest observed AF values below 0.01
Sources
BS1 The population frequency is below the 0.3% BS1 threshold used for this generic non-VCEP review. The highest observed population frequency was 0.09023% in gnomAD v2.1 East Asian individuals and 0.05125% in gnomAD v4.1 East Asian individuals. Details ▾Hide ▴
Rule
BS1 requires allele frequency greater than the benign strong threshold.
Evidence considered
- Highest observed AF values below 0.003
Sources
BS2 This variant was not observed in homozygous state in the reviewed population data, and no evidence was identified showing the full disease-relevant genotype in healthy individuals, so BS2 was not met. Details ▾Hide ▴
Rule
BS2 requires observation in healthy individuals inconsistent with a fully penetrant disease model.
Evidence considered
- Zero homozygotes in gnomAD v2.1 and v4.1
Still missing
- Need observations in healthy adults with the disease-relevant genotype
- if appropriate for the disorder.
Sources
Not assessed · 14 · no assessment recorded
PS1 No evidence was identified showing that a different nucleotide change causing the same amino acid substitution has already been established as pathogenic or likely pathogenic, so PS1 was not assessed. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant.
Evidence considered
- ClinVar record reviewed for this variant
Still missing
- Need evidence for another pathogenic nucleotide change encoding p.Arg2021Gln.
Sources
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Rule
PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history, with confirmed maternity and paternity.
Evidence considered
- ClinVar review did not provide confirmed de novo evidence
Still missing
- Need case-level de novo data with confirmed maternity and paternity.
Sources
PS3 No well-established functional studies were identified showing a damaging effect of p.(Arg2021Gln), so PS3 was not assessed. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies supportive of a damaging effect.
Evidence considered
- No variant-specific functional evidence retrieved
Still missing
- Need published functional data directly evaluating this variant.
Sources
PM3 No case-level evidence was identified showing this variant in trans with a pathogenic or likely pathogenic SPG11 variant in an affected individual, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3 requires observation in trans with a pathogenic variant for a recessive disorder.
Evidence considered
- No phase or trans observations available from reviewed sources
Still missing
- Need confirmed phase and companion variant data in affected individuals.
Sources
PM5 No evidence was identified showing a different pathogenic missense change at codon 2021, so PM5 was not assessed. Details ▾Hide ▴
Rule
PM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has already been seen.
Evidence considered
- ClinVar record for this exact variant reviewed
Still missing
- Need established pathogenic missense variation at the same codon.
Sources
PM6 No presumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Rule
PM6 requires presumed de novo occurrence without full confirmation.
Evidence considered
- No de novo evidence identified in reviewed sources
Still missing
- Need case-level presumed de novo evidence.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Evidence considered
- No pedigree or segregation information identified
Still missing
- Need family-based co-segregation data.
Sources
PP2 Available evidence was insufficient to show that SPG11 is a gene in which missense variation is a common disease mechanism and benign missense variation is uncommon, so PP2 was not assessed. Details ▾Hide ▴
Rule
PP2 requires a gene with low benign missense variation and a common missense disease mechanism.
Evidence considered
- SPG11 loss-of-function mechanism supported
- but missense-specific PP2 framework not established here
Still missing
- Need gene-level missense constraint or mechanism evidence supporting PP2.
Sources
pvs1_gene_context
PP4 No phenotype-specific clinical data were available to determine whether the observed presentation is highly specific for SPG11-related disease, so PP4 was not assessed. Details ▾Hide ▴
Rule
PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.
Still missing
- Need detailed phenotype and diagnostic specificity information.
BS3 No well-established functional studies were identified showing normal function for p.(Arg2021Gln), so BS3 was not assessed. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- No variant-specific benign functional evidence retrieved
Still missing
- Need published benign functional evidence directly evaluating this variant.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 requires lack of segregation in affected family members.
Evidence considered
- No family-based non-segregation evidence identified
Still missing
- Need family data showing lack of segregation with disease.
Sources
BP1 SPG11 loss of function is a known disease mechanism, but the available evidence was insufficient to conclude that missense variants are generally not disease-causing in this gene, so BP1 was not assessed. Details ▾Hide ▴
Rule
BP1 requires a missense variant in a gene for which truncating variants are primarily known to cause disease.
Evidence considered
- Gene-level loss-of-function mechanism supported
Still missing
- Need stronger gene-level evidence that pathogenic SPG11 variation is predominantly truncating with little support for missense causation.
Sources
pvs1_gene_context
BP2 No phase information was identified showing this variant in cis with a pathogenic variant or in trans in a context supporting BP2, so BP2 was not assessed. Details ▾Hide ▴
Rule
BP2 requires observation in cis with a pathogenic variant for a dominant disorder, or in trans with a pathogenic variant for a fully penetrant dominant disorder.
Evidence considered
- No cis/trans evidence identified
Still missing
- Need genotype and phase information from affected or unaffected individuals.
Sources
BP5 No evidence was identified for an alternate molecular explanation for the phenotype independent of this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
BP5 requires a variant in a case with an alternate molecular basis for disease.
Still missing
- Need case-level evidence for another established cause of the phenotype.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASPG11 loss of function is an established disease mechanism, but this variant is a missense substitution, p.(Arg2021Gln), and does not fall into the generic PVS1 null-variant categories. Available splice data do not indicate a loss-of-function splicing effect, so PVS1 is not applicable. Details ▾Hide ▴
Rule
PVS1 applies to predicted loss-of-function variants under the generic ClinGen SVI PVS1 framework; this missense variant does not meet that entry criterion.
Evidence considered
- SPG11 gene-level loss-of-function mechanism supported
- Missense variant outside nonsense/frameshift/canonical splice buckets
- Generic PVS1 scaffold did not support application
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Variant is p.(Arg2021Gln) missense
PP5 N/APP5 was not used in this review because assertion-only evidence from external classifications is not considered sufficient for criterion application. Details ▾Hide ▴
Rule
PP5 is not applied in this review workflow.
Evidence considered
- ClinVar assertions reviewed but not used as stand-alone evidence
Sources
BP3 N/AThis variant is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable. Details ▾Hide ▴
Rule
BP3 applies to in-frame deletions/insertions in repetitive regions without known function.
Evidence considered
- Variant is missense
- not in-frame indel
BP6 N/ABP6 was not used in this review because assertion-only benign classifications from external sources are not considered sufficient for criterion application. Details ▾Hide ▴
Rule
BP6 is not applied in this review workflow.
Evidence considered
- ClinVar assertions reviewed but not used as stand-alone evidence
Sources
BP7 N/AThis variant is missense rather than synonymous and does not meet the sequence context for BP7, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous variants with no predicted splice impact and no conservation concern.
Evidence considered
- Variant is p.(Arg2021Gln) missense
Identifiers
- Gene
- SPG11
- Transcript
- NM_025137.4
- Coding (HGVS c.)
- NM_025137.4:c.6062G>A
- Protein (HGVS p.)
- NP_079413.3:p.(Arg2021Gln)
- GRCh38
- chr15:44573690 C>T
- GRCh37
- chr15:44865888 C>T
Gene diagram
Every interpreted variant in SPG11, mapped onto the exon structure of NM_025137.4. Select a row to find it on the plot.
SPG11NM_025137.4
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 SPG11
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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
76 / 1,614,168 alleles
AF 4.71e-05 · 0 homozygotes · FAF 0.00035
gnomAD v2.1
25 / 282,728 alleles
AF 8.84e-05 · 0 homozygotes · FAF 0.000589
By genetic ancestry
gnomAD v4.1
AF 4.7e-05 · 76 / 1,614,168 alleles · 0 hom · FAF 0.00035
| East Asian23 / 44,878 | 0.00051 |
| Middle Eastern1 / 6,062 | 0.00016 |
| Admixed American8 / 60,016 | 0.00013 |
| Remaining individuals8 / 62,510 | 0.00013 |
| South Asian9 / 91,084 | 9.9e-05 |
| European (non-Finnish)26 / 1,180,038 | 2.2e-05 |
| African/African American1 / 75,032 | 1.3e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 8.8e-05 · 25 / 282,728 alleles · 0 hom · FAF 0.00059
| East Asian18 / 19,948 | 0.0009 |
| Remaining individuals1 / 7,218 | 0.00014 |
| Admixed American4 / 35,428 | 0.00011 |
| European (non-Finnish)2 / 129,072 | 1.5e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.70831e-05; MAF= 0.00471%, 76/1614168 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000512501; MAF= 0.05125%, 23/44878 alleles, homozygotes = 0); grpmax FAF= 0.00034976.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.84242e-05; MAF= 0.00884%, 25/282728 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000902346; MAF= 0.09023%, 18/19948 alleles, homozygotes = 0); grpmax FAF= 0.00058897.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple computational results support a benign interpretation. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, which together argue against a damaging protein or splice effect. Details ▾Hide ▴
Rule
BP4 was applied because multiple computational predictors support no impact on the gene or gene product.
Evidence considered
- REVEL 0.113 supports a benign missense interpretation
- BayesDel -0.445237 supports a benign interpretation
- SpliceAI max delta 0.02 argues against splice disruption
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL was 0.113, BayesDel was -0.445237, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.02, so PP3 was not met. Details ▾Hide ▴
Rule
PP3 requires multiple computational predictors supporting a deleterious effect on the gene or gene product.
Evidence considered
- REVEL 0.113
- BayesDel -0.445237
- SpliceAI max delta 0.02
Sources
BP7 N/AThis variant is missense rather than synonymous and does not meet the sequence context for BP7, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous variants with no predicted splice impact and no conservation concern.
Evidence considered
- Variant is p.(Arg2021Gln) missense
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.113. BayesDel score = -0.445237.
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
76 / 1,614,168 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 ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/659350/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-44865888-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-44573690-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_025137.4%3Ac.6062…
- OncoKB ↗www.oncokb.org/gene/SPG11/R2021Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SPG11+c.6062G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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= 4.70831e-05; MAF= 0.00471%, 76/1614168 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000512501; MAF= 0.05125%, 23/44878 alleles, homozygotes = 0); grpmax FAF= 0.00034976.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.84242e-05; MAF= 0.00884%, 25/282728 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000902346; MAF= 0.09023%, 18/19948 alleles, homozygotes = 0); grpmax FAF= 0.00058897.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.113. BayesDel score = -0.445237.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.