Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000465.3 | Alternative | 5523 nt | 143–2476 |
| NM_000465.2 | Alternative | 2610 nt | 136–2469 |
| NM_000465.4 | MANE Select | 5478 nt | 115–2448 |
| NM_000465.1 | Alternative | 2530 nt | 74–2407 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as 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 | 326 bp |
| Donor Loss (DL) | 0.0 | 230 bp |
| Acceptor Gain (AG) | 0.0 | 34 bp |
| Donor Gain (DG) | 0.0 | 447 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1 – 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 (P709=) that does not introduce a stop codon or affect splice sites. Therefore, this criterion is not applied because the variant is not a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: it does not change the amino acid (synonymous). Therefore, this criterion is not applied because there is no amino acid change.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'PS2 – 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 about de novo occurrence. Therefore, this criterion is not applied due to lack of de novo data.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: 'PS3 – 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 because functional data are unavailable.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case–control data or enriched prevalence in affected individuals. Therefore, this criterion is not applied due to lack of prevalence data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: it is a synonymous change outside of any known functional domain. Therefore, this criterion is not applied.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no data on trans configuration with another variant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is synonymous with no change in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'PM5 – 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, the rule for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 – 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. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)'. The evidence for this variant shows: computational tools predict no impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'PP4 – Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype or family history data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'BA1 – Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: allele frequency is absent, not greater than expected. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: 'BS2 – Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: no data on observation in healthy controls with clinical evaluation. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'BS3 – 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, the rule for BS4 is: 'BS4 – Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 – 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, the rule for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: it is a single-nucleotide synonymous variant. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: in silico tools including SpliceAI predict no effect on splicing and CADD score is low. Therefore, this criterion is applied at Supporting strength because multiple computational predictions indicate no impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such cases reported. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: ClinVar entries list it as Likely benign (2 labs) and Benign (1 lab) without underlying data. Therefore, this criterion is applied at Supporting strength because reputable sources report it as benign.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is synonymous (P709=) and SpliceAI scores are zero for splice impact. Therefore, this criterion is applied at Supporting strength because it is a silent change with no predicted splicing effect.