rs121965090
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_004628.5(XPC):c.1177C>T(p.Arg393Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,848 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R393Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_004628.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPC | NM_004628.5 | c.1177C>T | p.Arg393Trp | missense_variant | 9/16 | ENST00000285021.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPC | ENST00000285021.12 | c.1177C>T | p.Arg393Trp | missense_variant | 9/16 | 1 | NM_004628.5 | P1 | |
XPC-AS1 | ENST00000627116.2 | n.457-7170G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000928 AC: 141AN: 152020Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000883 AC: 220AN: 249252Hom.: 0 AF XY: 0.000850 AC XY: 115AN XY: 135220
GnomAD4 exome AF: 0.00136 AC: 1984AN: 1461710Hom.: 2 Cov.: 32 AF XY: 0.00130 AC XY: 946AN XY: 727136
GnomAD4 genome ? AF: 0.000927 AC: 141AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.000793 AC XY: 59AN XY: 74368
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces arginine with tryptophan at codon 393 of the XPC protein (p.Arg393Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121965090, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with XPC-related conditions. ClinVar contains an entry for this variant (Variation ID: 135484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XPC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies support a damaging effect: moderate reduction in recruitment of XPC protein to focal DNA damage (Qiao et al., 2011); Observed in individuals with colorectal, bladder, and other cancers, as well as in healthy controls (Qiao et al., 2011; Bodian et al., 2014; Matejcic et al., 2021); This variant is associated with the following publications: (PMID: 21273643, 35530314, 24728327, 33627384) - |
Xeroderma pigmentosum, group C Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 09, 2021 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 10, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 03, 2022 | Variant summary: XPC c.1177C>T (p.Arg393Trp) 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 0.00088 in 249252 control chromosomes. The observed variant frequency is approximately 1.25 fold of the estimated maximal expected allele frequency for a pathogenic variant in XPC causing Xeroderma Pigmentosum phenotype (0.00071), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.1177C>T in individuals affected with Xeroderma Pigmentosum has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The authors report a moderate reduction in recruitment of XPC protein to focal DNA damage in an in-vitro system utilizing GFP-tagged XPC plasmids (Qiao_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Xeroderma pigmentosum Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 25, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at