Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000535.6 | Alternative | 5156 nt | 88–2676 |
| NM_000535.4 | Alternative | 2836 nt | 88–2676 |
| NM_000535.7 | MANE Select | 5093 nt | 31–2619 |
| NM_000535.5 | Alternative | 2851 nt | 88–2676 |
| NM_000535.3 | Alternative | 2820 nt | 57–2645 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar 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) | 0.02 | 109 bp |
| Donor Loss (DL) | 0.0 | 10 bp |
| Acceptor Gain (AG) | 0.0 | 14 bp |
| Donor Gain (DG) | 0.0 | -327 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Variants at IVS±1 or IVS±2 where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD." The evidence for this variant shows it is at position +10, outside of IVS±1 or IVS±2. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI." The evidence for this variant shows it is at +10, not affecting a known non-canonical splice nucleotide. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "De novo points: ≥4 de novo points for Very Strong, 2–3 for Strong, 1 for Moderate, 0.5 for Supporting." There are no de novo data available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Calibrated functional assays with functional odds for Pathogenicity >18.7; Moderate/Supporting with lower thresholds." No functional assay data exist for this variant. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals statistically increased over controls." No case-control or cohort data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or functional domain without benign variation." The variant is intronic outside known functional motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence shows the variant is absent from gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Evidence for recessive inheritance based on allelic observations." No trans observations in recessive cases are available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss." This intronic variant does not alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Missense change at a residue with a different pathogenic missense." This variant is intronic. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Unconfirmed de novo occurrence." No parental data exist. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense in a gene with low rate of benign missense variants." This variant is intronic. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Predicted splice defect for non-canonical splice nucleotides using SpliceAI delta score ≥0.2." SpliceAI predicts a delta score of 0.02. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Phenotype specificity with multiple independent tumors or protein loss patterns." No tumor or phenotype data are available. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The variant is reported benign, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "GnomAD v4 Grpmax filtering allele frequency ≥0.0028." The allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001." The allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with a known pathogenic variant in the same gene in LS cases without CMMRD." No such co-occurrence data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Synonymous/intronic variants with no mRNA aberration in laboratory assays." No laboratory splicing assays have been performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of co-segregation with disease in families." No segregation data 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 truncating variants cause disease." This variant is intronic. 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." No data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions." This variant is not an indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting: For intronic variants, SpliceAI predicts no impact with delta score ≤0.1." SpliceAI gives 0.02. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Observations in cases with an alternate molecular basis for disease." No such cases are reported. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." ClinVar entries report this variant as Likely Benign. Therefore, this criterion is applied at Supporting strength.
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: "Supporting: A synonymous or intronic variant at or beyond -21/+7." This variant is at +10. Therefore, this criterion is applied at Supporting strength.