Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_005475.3 | MANE Select | 5431 nt | 383–2110 |
| NM_005475.1 | Alternative | 5423 nt | 358–2085 |
| NM_005475.2 | RefSeq Select | 5425 nt | 358–2085 |
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 | 218 bp |
| Donor Loss (DL) | 0.0 | 242 bp |
| Acceptor Gain (AG) | 0.0 | 198 bp |
| Donor Gain (DG) | 0.0 | 484 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, 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 or multi-exon deletion)". The evidence for this variant shows: NM_005475.2:c.-113_-86del is a non-coding 5′ UTR deletion not predicted to abolish the coding sequence or canonical splice sites. Therefore, this criterion is not applied because the variant does not create a null effect in a gene with established LoF mechanism.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no amino acid change occurs as it is a non-coding deletion. Therefore, this criterion is not applied because there is no amino acid change to compare to known pathogenic variants.
PS2 (Not Applied)
According to standard ACMG guidelines, 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: no de novo occurrence or parental testing data are available. Therefore, this criterion is not applied due to lack of confirmed de novo evidence.
PS3 (Not Applied)
According to standard ACMG guidelines, 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 characterization studies have been performed. Therefore, this criterion is not applied because functional impact has not been assessed.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied due to absence of evidence for increased prevalence in affected individuals.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation". The evidence for this variant shows: the deletion lies in the 5′ UTR, outside known functional domains or mutational hotspots. Therefore, this criterion is not applied because the variant is not in a recognized functional region.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "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: NM_005475.2:c.-113_-86del is not found in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls, supporting rarity.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: no trans observations with a known pathogenic allele have been reported. Therefore, this criterion is not applied due to lack of trans configuration data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: the deletion is in the 5′ UTR and does not alter protein length. Therefore, this criterion is not applied because there is no impact on protein length.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before". The evidence for this variant shows: it is not a missense change. Therefore, this criterion is not applied because there is no missense alteration to evaluate.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data or parental testing is available. Therefore, this criterion is not applied due to absence of assumed de novo evidence.
PP1 (Not Applied)
According to standard ACMG guidelines, 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 because segregation has not been assessed.
PP2 (Not Applied)
According to standard ACMG guidelines, 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 not a missense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". The evidence for this variant shows: in silico prediction (SpliceAI score 0) and other computational analyses predict no impact. Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or clinical presentation information is provided. Therefore, this criterion is not applied due to lack of phenotype data.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied because no reputable source has classified it as pathogenic.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (stand-alone)". The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied because allele frequency is not high.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency greater than expected for disorder". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: no healthy individual observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, 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 performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation studies exist. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: it is not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: located in 5′ UTR, not within a defined repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, 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: SpliceAI predicts no impact on splicing (score 0) and other in silico analyses indicate no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence consistently predicts a benign impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports with an alternate molecular cause. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: not reported by any reputable source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a non-coding UTR deletion, not a synonymous coding change. Therefore, this criterion is not applied.