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 (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) | 0.01 | 167 bp |
| Donor Loss (DL) | 0.0 | 333 bp |
| Acceptor Gain (AG) | 0.0 | 155 bp |
| Donor Gain (DG) | 0.0 | 58 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: variant consequence and type are unknown, with no indication of a null effect. Therefore, this criterion is not applied because the variant is not demonstrated to be a null LoF 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: the amino acid change is unknown. Therefore, this criterion is not applied because there is no information on an amino acid change matching a known pathogenic variant.
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 de novo or parental testing data are available. Therefore, this criterion is not applied because de novo status cannot be assessed.
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 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 affected individual prevalence data. Therefore, this criterion is not applied because there is no evidence of enrichment in affected individuals.
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 and domain context are unknown. Therefore, this criterion is not applied because it is not located in a known mutational hot spot or functional domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "PM2 – Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The evidence for this variant shows: variant not found in population databases (gnomAD). 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 because there is no evidence of trans occurrence in a recessive context.
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 in-frame indel or stop-loss. Therefore, this criterion is not applied because no protein length change is present.
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: variant consequence is unknown and no missense change identified. Therefore, this criterion is not applied because no missense change is characterized.
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 because assumed de novo status cannot be assessed.
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 because co-segregation has not been evaluated.
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: consequence unknown and no missense context defined. Therefore, this criterion is not applied because missense status and gene-specific constraint are not established.
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 predictors show mixed results with SpliceAI predicting no 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 phenotype or family history provided. Therefore, this criterion is not applied because clinical specificity is not available.
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 reporting pathogenic. Therefore, this criterion is not applied because no pathogenic assertion exists.
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%. Therefore, this criterion is not applied because population frequency is not above threshold.
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 = 0%. Therefore, this criterion is not applied because allele frequency is not higher than expected.
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 healthy individual data. Therefore, this criterion is not applied because no observation in healthy individuals is available.
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 performed. Therefore, this criterion is not applied because functional evidence is not available.
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 because family segregation has not been assessed.
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: consequence unknown. Therefore, this criterion is not applied because missense status and mechanism are unclear.
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 phasing data. Therefore, this criterion is not applied because cis/trans status is not determined.
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: no in-frame indel. Therefore, this criterion is not applied because the variant is not an in-frame indel.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: in silico predictors show mixed results and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational tools collectively indicate no functional effect.
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 case report with alternate molecular cause. Therefore, this criterion is not applied because no alternate diagnosis context exists.
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: reported as Likely Benign in ClinVar by one clinical laboratory with no primary data. Therefore, this criterion is applied at Supporting strength because a reputable source asserts benign status without available data.
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: variant is intronic (+19), not synonymous. Therefore, this criterion is not applied because it is not a synonymous exonic change.