Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000548.3 | Alternative | 5675 nt | 107–5530 |
| NM_000548.2 | Alternative | 5543 nt | 19–5442 |
| NM_000548.4 | Alternative | 5751 nt | 201–5624 |
| NM_000548.5 | MANE Select | 6415 nt | 111–5534 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain significance (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 | 15 bp |
| Donor Loss (DL) | 0.02 | -317 bp |
| Acceptor Gain (AG) | 0.14 | -106 bp |
| Donor Gain (DG) | 0.01 | -56 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 or multi-exon deletion in a LoF gene)". The evidence for this variant shows: NM_000548.5:c.2356-15T>A is an intronic variant outside the canonical ±1/2 splice sites with no predicted splicing impact. Therefore, this criterion is not applied at Not Applied strength because the variant does not create a null allele as defined by the rule.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "PS1 – Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no amino acid change is produced or documented for this intronic variant. Therefore, this criterion is not applied at Not Applied strength because there is no matching pathogenic 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: no information regarding de novo occurrence is available. Therefore, this criterion is not applied at Not Applied strength due to lack of de novo confirmation.
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 at Not Applied strength because functional data are lacking.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "PS4 – Prevalence in affected individuals is significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data indicating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength 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 and/or well-established functional domain without benign variation". The evidence for this variant shows: c.2356-15T>A is located in a non-canonical intronic region with no known functional domain annotation. Therefore, this criterion is not applied at Not Applied strength because it is not in a defined hotspot or domain.
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: present in gnomAD at MAF=0.0143%, extremely rare and absent from other control datasets. Therefore, this criterion is applied at Moderate strength because the allele frequency is below thresholds 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 data on phasing with another variant. Therefore, this criterion is not applied at Not Applied strength due to lack of trans observation.
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 an intronic SNV with no effect on protein length. Therefore, this criterion is not applied at Not Applied strength.
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 before". The evidence for this variant shows: not a missense change. Therefore, this criterion is not applied at Not Applied strength.
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 data. Therefore, this criterion is not applied at Not Applied strength.
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: family segregation data are not available. Therefore, this criterion is not applied at Not Applied strength.
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 non-coding. Therefore, this criterion is not applied at Not Applied strength.
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 or gene product". The evidence for this variant shows: CADD score 0.33 and SpliceAI max 0.14 predict no deleterious effect. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not indicate harm.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "PP4 – 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 information. Therefore, this criterion is not applied at Not Applied strength.
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: ClinVar reports benign and VUS, no pathogenic reports. Therefore, this criterion is not applied at Not Applied strength.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "BA1 – Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0.0143% which is well below the BA1 threshold. Therefore, this criterion is not applied at Not Applied strength.
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=0.0143% which is not greater than expected. Therefore, this criterion is not applied at Not Applied strength.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "BS2 – 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 data on observation in healthy individuals. Therefore, this criterion is not applied at Not Applied strength.
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. Therefore, this criterion is not applied at Not Applied strength.
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 at Not Applied strength.
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 intronic. Therefore, this criterion is not applied at Not Applied strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "BP2 – 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 at Not Applied strength.
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: single nucleotide substitution in an intron. Therefore, this criterion is not applied at Not Applied strength.
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: CADD score 0.33 and SpliceAI max 0.14 predict no impact. Therefore, this criterion is applied at Supporting strength because in silico tools uniformly indicate lack of 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 data with alternate diagnoses. Therefore, this criterion is not applied at Not Applied strength.
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: ClinVar reports are available and conflict, so no single unsubstantiated benign report. Therefore, this criterion is not applied at Not Applied strength.
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: not a synonymous change. Therefore, this criterion is not applied at Not Applied strength.