Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_003620.2 | Alternative | 3163 nt | 223–2040 |
| NM_003620.4 | MANE Select | 4768 nt | 223–2040 |
| NM_003620.3 | RefSeq Select | 4790 nt | 233–2050 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (1 clinical laboratories)."
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 | 499 bp |
| Donor Loss (DL) | 0.0 | 228 bp |
| Acceptor Gain (AG) | 0.0 | -41 bp |
| Donor Gain (DG) | 0.0 | -2 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines for PVS1, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a synonymous change (Gly61=) and does not introduce a premature stop codon or affect canonical splice sites. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines for PS1, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: it is a synonymous change with no amino acid alteration (Gly61=), and there is no known pathogenic variant at this codon. Therefore, this criterion is not applied because there is no amino acid change.
PS2 (Not Applied)
According to standard ACMG guidelines for PS2, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: there is no information regarding de novo occurrence or parental testing. Therefore, this criterion is not applied because de novo status has not been evaluated.
PS3 (Not Applied)
According to standard ACMG guidelines for PS3, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to absence of functional data.
PS4 (Not Applied)
According to standard ACMG guidelines for PS4, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or affected individual prevalence data are available. Therefore, this criterion is not applied because there is no data on increased prevalence in cases.
PM1 (Not Applied)
According to standard ACMG guidelines for PM1, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: there is no indication that codon 61 resides in a known mutational hotspot or critical functional domain. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines for PM2, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is observed at a very low frequency in gnomAD (MAF=0.00129%, 2/154,686 alleles; MAF=0.00335% in European non-Finnish). Therefore, this criterion is applied at Moderate strength because the variant is present at an extremely low frequency in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines for PM3, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on trans configuration with another pathogenic variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines for PM4, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is synonymous without affecting protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines for PM5, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: it is synonymous and not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines for PM6, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental testing information. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines for PP1, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines for PP2, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: it is synonymous, not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines for PP3, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: in silico predictions (CADD=0.55, SpliceAI=0.00) suggest no deleterious effect. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines for PP4, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no patient phenotype or clinical context is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines for PP5, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar reports it as Likely Benign, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines for BA1, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF=0.00129% is well below thresholds for BA1. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines for BS1, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF=0.00129% is not greater than expected for a dominant disorder. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines for BS2, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: presence in population databases without phenotype information does not confirm healthy status with full penetrance. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines for BS3, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies have been conducted. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines for BS4, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation studies are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines for BP1, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines for BP2, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis or trans with another variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines for BP3, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a single-nucleotide change, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines for BP4, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: in silico predictors yield CADD=0.55 and SpliceAI=0.00, indicating no functional impact. Therefore, this criterion is applied at Supporting strength because computational data consistently predict no effect.
BP5 (Not Applied)
According to standard ACMG guidelines for BP5, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case information is available. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines for BP6, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar lists it as Likely Benign by one clinical laboratory without underlying evidence. Therefore, this criterion is applied at Supporting strength because a reputable database reports benign classification without independent evidence.
BP7 (Supporting)
According to standard ACMG guidelines for BP7, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a synonymous change and SpliceAI predicts no impact on splicing (scores=0.00). Therefore, this criterion is applied at Supporting strength because the variant is synonymous with no splicing effect.