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"This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as 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) | 0.15 | 10 bp |
| Donor Loss (DL) | 0.15 | -141 bp |
| Acceptor Gain (AG) | 0.0 | -2 bp |
| Donor Gain (DG) | 0.0 | -2 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: it is a synonymous change (p.S869=) with SpliceAI predicting no impact on splicing. Therefore, this criterion is not applied because PVS1 applies only to null variants predicted to undergo NMD or loss-of-function, which is not the case for a synonymous variant with no splicing effect.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong Use PALB2 PS1 Splicing table Modification Type: General recommendation". The evidence for this variant shows: it does not lead to an amino acid change and there is no known pathogenic variant at this nucleotide resulting in the same amino acid. Therefore, this criterion is not applied because PS1 requires the same amino acid change as a known pathogenic variant.
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 parental testing or de novo data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo 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 unavailable.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5)". The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied due to absence of case-control evidence.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain without benign variation". The evidence for this variant shows: it is a synonymous change outside of any known functional domain or hotspot. Therefore, this criterion is not applied because the variant is not in a critical domain or hotspot.
PM2 (Not Applied)
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: gnomAD MAF=0.00353% (10/282,886 alleles), which exceeds the VCEP threshold of ≤0.00033%. Therefore, this criterion is not applied because the allele frequency is above the supporting threshold.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Strong Strength: Strong Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: PM3 applies to recessive Fanconi anemia compound heterozygosity data, which are not available. Therefore, this criterion is not applied due to lack of trans-allelic data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants". The evidence for this variant shows: it is a synonymous change with no protein length alteration. Therefore, this criterion is not applied because there is no change in protein length.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Supporting Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183". The evidence for this variant shows: it is synonymous and does not introduce a premature stop. Therefore, this criterion is not applied because PM5 is specific to truncating variants.
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: there is no information on de novo occurrence. Therefore, this criterion is not applied due to absence of de novo data.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Strong Strength: Strong LOD ≥1.26 or Bayes Factor (LR) ≥18:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied because family segregation analysis is lacking.
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 synonymous, not missense. Therefore, this criterion is not applied because PP2 pertains to missense variants.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: Do not use. RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing". The evidence for this variant shows: SpliceAI predicts no impact on splicing (max score 0.15). Therefore, this criterion is not applied because computational evidence does not suggest a 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-level specificity is provided. Therefore, this criterion is not applied due to lack of phenotype correlation.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation". The evidence for this variant shows: ClinVar reports it as benign/likely benign only. Therefore, this criterion is not applied because no reputable source reports pathogenicity.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone GnomAD Filtering Allele Frequency >0.1%". The evidence for this variant shows: gnomAD MAF=0.00353% (0.0000353), which is below the 0.1% threshold. Therefore, this criterion is not applied because the allele frequency does not exceed the BA1 threshold.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong GnomAD Filtering Allele Frequency greater than expected for disease >0.01%". The evidence for this variant shows: gnomAD MAF=0.00353% (0.0000353), which is below 0.01%. Therefore, this criterion is not applied because the allele frequency does not exceed the BS1 threshold.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Per Fanconi Anemia BS2 tables". The evidence for this variant shows: no homozygote or healthy carrier data as per Fanconi anemia BS2 tables. Therefore, this criterion is not applied due to lack of appropriate population genotype data.
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 performed. Therefore, this criterion is not applied because functional evidence is missing.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong LOD ≤ -1.28 or Bayes Factor (LR) ≤ 0.053:1". The evidence for this variant shows: no segregation or lack-of-segregation data. Therefore, this criterion is not applied due to absence of segregation analysis.
BP1 (Not Applied)
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Supporting Apply to all missense variants. Modification Type: Gene-specific". The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied because BP1 pertains only to missense changes.
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 in any mechanism". The evidence for this variant shows: no data on phasing with other variants. Therefore, this criterion is not applied due to lack of cis/trans data.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function". The evidence for this variant shows: it is a single-nucleotide synonymous change, not an indel. Therefore, this criterion is not applied because BP3 is not relevant.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing". The evidence for this variant shows: SpliceAI predicts no splicing impact (max score 0.15). Therefore, this criterion is applied at Supporting strength because computational splice analysis indicates no effect.
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 data are provided. Therefore, this criterion is not applied due to lack of alternate molecular findings.
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to perform an independent evaluation". The evidence for this variant shows: ClinVar contains multiple submissions (6 likely benign, 2 benign) without shared primary data. Therefore, this criterion is applied at Supporting strength because reputable sources classify this variant as benign without accessible evidence.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and nucleotide not highly conserved". The evidence for this variant shows: while it is synonymous and no splicing impact is predicted, conservation data are not provided. Therefore, this criterion is not applied due to insufficient conservation information required by BP7.