Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_004628(XPC):c.1496C>T(p.Ala499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 151730 control chromosomes in the gnomAD Genomes database, including 4135 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A499T) has been classified as Likely benign.
Verdict is Benign. Variant got -20 ACMG points.
GnomAD3 genomes AF: 0.215AC: 32678AN: 151730Hom.: 4135Cov.: 32 GnomAD3 exomes AF: 0.244AC: 60666AN: 249122Hom.: 7936 AF XY: 0.243AC XY: 32906AN XY: 135152 GnomAD4 exome AF: 0.247AC: 360862AN: 1461616Hom.: 46184 AF XY: 0.246AC XY: 178638AN XY: 727082
Submissions by phenotype
|Benign, criteria provided, single submitter||clinical testing||PreventionGenetics, PreventionGenetics||-||- -|
|Benign, criteria provided, single submitter||clinical testing||Women's Health and Genetics/Laboratory Corporation of America, LabCorp||Aug 27, 2018||Variant summary: XPC c.1496C>T (p.Ala499Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.24 in 276928 control chromosomes in the gnomAD database, including 8807 homozygotes. The observed variant frequency is approximately 171-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.0014), strongly suggesting that the variant is benign. The variant has been indicated to be associated with an increased risk of cancer (He_2013). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -|
|not provided, no assertion provided||reference population||ITMI||Sep 19, 2013||- -|
|Benign, criteria provided, single submitter||clinical testing||GeneDx||Feb 26, 2019||This variant is associated with the following publications: (PMID: 26001739, 23436679, 27153395, 15700316, 20369554, 20193233, 24728327, 23400628, 17575242, 21113018, 19706757, 17882560) -|
|Benign, criteria provided, single submitter||clinical testing||Invitae||Nov 04, 2022||- -|
Xeroderma pigmentosum, group C
|Benign, criteria provided, single submitter||clinical testing||Illumina Laboratory Services, Illumina||Mar 06, 2018||This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -|
|Benign, criteria provided, single submitter||clinical testing||Genome-Nilou Lab||Dec 05, 2021||- -|
Xeroderma pigmentosum group A
|Benign, criteria provided, single submitter||clinical testing||KCCC/NGS Laboratory, Kuwait Cancer Control Center||Jul 07, 2023||- -|
Find out detailed SpliceAI scores and Pangolin per-transcript scores at