Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001904.3 | Alternative | 3720 nt | 269–2614 |
| NM_001904.4 | MANE Select | 3661 nt | 215–2560 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (3 clinical laboratories) and as Likely benign (2 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 | 300 bp |
| Donor Loss (DL) | 0.0 | 30 bp |
| Acceptor Gain (AG) | 0.0 | 119 bp |
| Donor Gain (DG) | 0.0 | 453 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: NM_001904.4:c.1155C>A is a synonymous variant (L385=), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the rule for null variants.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: L385= does not change the amino acid. 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: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no data on de novo occurrence or parental testing. Therefore, this criterion is not applied because de novo status cannot be evaluated without parental data.
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 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: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data. Therefore, this criterion is not applied because case prevalence data are not available.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: c.1155C>A lies in a region without known mutational hot spot or domain annotation. Therefore, this criterion is not applied because the variant is not within a recognized hot spot or domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: present in gnomAD at MAF=0.0403% overall and absent in homozygotes, which is below the 0.1% threshold. Therefore, this criterion is applied at Moderate strength because the allele frequency is extremely low in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on trans configuration with other variants. Therefore, this criterion is not applied because phasing data are not available.
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: synonymous change with no change in protein length. Therefore, this criterion is not applied because there is no protein length alteration.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no amino acid change. Therefore, this criterion is not applied.
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 information. Therefore, this criterion is not applied because de novo status is unevaluable without any parental data.
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 segregation data. Therefore, this criterion is not applied because family segregation information is not available.
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: synonymous variant, not missense. 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". The evidence for this variant shows: CADD score 0.37 and SpliceAI score 0 predict no deleterious effect. 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: "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 clinical information provided. Therefore, this criterion is not applied because phenotype data are not available.
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: ClinVar reports benign/likely benign only. Therefore, this criterion is not applied because no reputable source reports it as pathogenic.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0.0403%, which is below typical BA1 thresholds (e.g., >5%). Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: MAF is low (0.0403%) and does not exceed disorder-specific thresholds. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals with full penetrance expected at an early age". The evidence for this variant shows: no confirmed healthy adult homozygotes or phenotyped individuals. 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 assays 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 family segregation data. 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: synonymous change, 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 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: "In-frame indels in repetitive region without known function". The evidence for this variant shows: not an indel. 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". The evidence for this variant shows: CADD score 0.37 and SpliceAI score 0 predict no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational tools predict no functional 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 alternate diagnosis. Therefore, this criterion is not applied.
BP6 (Supporting)
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: ClinVar entries report benign (3 labs) and likely benign (2 labs) without underlying data. Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as benign without available primary evidence.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing and no conservation at the nucleotide level". The evidence for this variant shows: L385= is synonymous and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because it is a synonymous change without splicing impact.