Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_024675.4 | MANE Select | 4008 nt | 154–3714 |
| NM_024675.3 | RefSeq Select | 4069 nt | 201–3761 |
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 | 151 bp |
| Donor Loss (DL) | 0.0 | 282 bp |
| Acceptor Gain (AG) | 0.0 | -309 bp |
| Donor Gain (DG) | 0.0 | 69 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength" (applicable to null variants). The evidence for this variant shows: missense change D1168Y, not a null variant. Therefore, this criterion is not applied.
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 previously established pathogenic variant at codon 1168. Therefore, this criterion is not applied.
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". The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
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 available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls". The evidence for this variant shows: no case-control or cohort data 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 and/or critical and well-established functional domain". The evidence for this variant shows: D1168Y is not located in a known hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Variant absent in gnomAD or present in ≤ 1/300,000 alleles". The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because of absence from population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder". The evidence for this variant shows: not a recessive scenario. 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 nonsense variants". The evidence for this variant shows: missense substitution without protein length change. Therefore, this criterion is not applied.
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 other pathogenic missense at D1168. 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.
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 available. Therefore, this criterion is not applied.
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 pathogenic missense variants are common". The evidence for this variant shows: insufficient data to assess missense constraint. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Protein: Do not use. RNA: At least one well-established in silico predictor shows impact on splicing". The evidence for this variant shows: SpliceAI predicts no impact on splicing. Therefore, this criterion is not applied.
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 data provided. 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 evidence for this variant shows: not found in ClinVar. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: GnomAD Filtering Allele Frequency >0.1%". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: GnomAD Filtering Allele Frequency greater than expected for disease >0.01%". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Per Fanconi Anemia BS2 tables". The evidence for this variant shows: no healthy individual data. 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 gene or gene product". The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong: LOD ≤ -1.28 or Bayes Factor ≤0.053:1". The evidence for this variant shows: no segregation or non-segregation data available. Therefore, this criterion is not applied.
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Apply to all missense variants". The evidence for this variant shows: D1168Y is a missense substitution. Therefore, this criterion is applied at Supporting strength because it is a missense in a LOF gene.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder". The evidence for this variant shows: no trans observation. 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". The evidence for this variant shows: missense substitution. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "RNA: At least one well-established in silico predictor shows no impact on splicing". The evidence for this variant shows: SpliceAI predicts no splicing impact (scores 0). Therefore, this criterion is applied at Supporting strength because of the lack of predicted splicing 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 such case. 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". The evidence for this variant shows: not in ClinVar. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous and deep intronic variants with no splice impact". The evidence for this variant shows: missense substitution. Therefore, this criterion is not applied.