Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000059.4 | MANE Select | 11954 nt | 200–10456 |
| NM_000059.2 | Alternative | 11386 nt | 228–10484 |
| NM_000059.3 | RefSeq Select | 11386 nt | 228–10484 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratories) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -127 bp |
| Donor Loss (DL) | 0.0 | 439 bp |
| Acceptor Gain (AG) | 0.0 | -400 bp |
| Donor Gain (DG) | 0.0 | -311 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1,2 splice sites) in genes where LOF is a known mechanism. The evidence for this variant shows that it is a synonymous change (Q1037=), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. The evidence for this variant shows it is synonymous (no amino acid change) and there is no known pathogenic variant with identical splicing impact. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrence. The evidence for this variant shows no information on de novo status. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, PS3 applies when well-established functional studies demonstrate a damaging effect. The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, PS4 applies when the variant is significantly enriched in cases versus controls. The evidence for this variant shows no case-control data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 applies when a variant is located in a well‐established functional domain without benign variation. The evidence for this variant shows it is synonymous and located outside defined domains. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, PM2_Supporting applies to variants absent from controls in gnomAD. The evidence for this variant shows it is observed at MAF=0.000401% in gnomAD. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, PM3 applies for recessive evidence in BRCA2-related Fanconi Anemia co-occurrence. The evidence for this variant shows no FA phenotype or co-occurrence data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 applies when there is a protein length change not due to LOF. The evidence for this variant shows no change in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, PM5 applies for novel missense changes at residues where different pathogenic missense changes have been seen. The evidence for this variant shows it is synonymous, not missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 applies to assumed de novo without confirmation. The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies for co-segregation with disease. The evidence for this variant shows no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies for missense variants in genes with low benign missense rates. The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 applies for computational evidence of deleterious impact. The evidence for this variant shows SpliceAI=0 and BayesDel no-AF<0.30, predicting no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, PP4 applies for phenotype specificity in breast cancer. The evidence for this variant shows no phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic. The evidence for this variant shows ClinVar reports it as benign/likely benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies for allele frequency >0.1% in non-founder populations. The evidence for this variant shows MAF=0.00618% in African/African American. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies for FAF>0.01%. The evidence for this variant shows MAF<0.01%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies in absence of recessive phenotype (Fanconi Anemia) evidence. The evidence for this variant shows no phenotype or FA testing. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies when functional studies show no damaging effect. The evidence for this variant shows no functional assays. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies for lack of segregation. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1 (Strong)
According to VCEP guidelines, BP1_Strong: 'Apply BP1_Strong for silent substitution outside a potentially clinically important functional domain AND no splicing predicted (SpliceAI≤0.1)'. The evidence for this variant shows it is a silent substitution at Q1037 (outside domains aa10-40 and aa2481-3186) with SpliceAI=0. Therefore, this criterion is applied at Strong strength because it meets the rule conditions.
BP2 (Not Applied)
According to standard ACMG guidelines, BP2 applies for observation in trans with a pathogenic variant. The evidence for this variant shows no such co-occurrence. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies for in-frame indels in repetitive regions. The evidence for this variant shows it is synonymous. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows SpliceAI predicts no splicing impact and CADD score of -0.07 indicating lack of deleteriousness. Therefore, this criterion is applied at Supporting strength because computational evidence supports no impact.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when a variant is found in trans with another pathogenic variant in a case-based context. The evidence for this variant shows no co-occurrence clinical data. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, BP6: 'Reputable source recently reports variant as benign'. The evidence for this variant shows ClinVar reports it as Likely benign/Benign by multiple laboratories and ENIGMA expert panel. Therefore, this criterion is applied at Supporting strength because of reputable classification without available primary data.
BP7 (Supporting)
According to standard ACMG guidelines, BP7: 'A synonymous variant for which splicing prediction algorithms predict no impact on splicing'. The evidence for this variant shows it is synonymous with SpliceAI=0 predicting no splicing impact. Therefore, this criterion is applied at Supporting strength because it meets the rule conditions.