Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006265.3 | MANE Select | 3660 nt | 199–2094 |
| NM_006265.2 | RefSeq Select | 3773 nt | 289–2184 |
| NM_006265.1 | Alternative | 3647 nt | 185–2080 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
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 | -16 bp |
| Donor Loss (DL) | 0.0 | -165 bp |
| Acceptor Gain (AG) | 0.08 | -22 bp |
| Donor Gain (DG) | 0.0 | 233 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: c.1471-16T>C is an intronic change outside the canonical ±1/2 splice sites and does not create a premature stop codon. 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, 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: there is no reported amino acid change or known pathogenic variant at this position. Therefore, this criterion is not applied because the variant does not result in a matching amino acid substitution.
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: no information on de novo occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo evidence.
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 assays have been performed. Therefore, this criterion is not applied because functional data are not available.
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 or disease cohort data are available. Therefore, this criterion is not applied due to absence 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: location at c.1471-16 is outside known functional domains and not a mutational hotspot. 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: MAF=0.00581% in gnomAD with no homozygotes, meeting the threshold for rarity. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
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 information on trans phase with another pathogenic 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: no coding insertion/deletion or stop-loss. 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: 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 or parental data. 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: intronic location, not missense. 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: in silico tools (SpliceAI score 0.08) predict no significant splicing impact. Therefore, this criterion is not applied because computational evidence does not support a deleterious effect.
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 patient phenotype data provided. 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: not present in ClinVar or other databases. 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: MAF=0.00581%, well below the >5% threshold. 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: MAF is extremely low. 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 healthy adult observation. 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 available. 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: intronic location. 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 information. 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: not an in-frame indel. 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: SpliceAI predicts no significant splicing impact (score 0.08) and other in silico tools are not predictive of deleteriousness. Therefore, this criterion is applied at Supporting strength because computational data indicate no functional 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 alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
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: absent from clinical databases. Therefore, this criterion is not applied.
BP7 (Not Applied)
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: intronic location, not synonymous. Therefore, this criterion is not applied.