rs755825264
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.463C>T(p.Arg155Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R155R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004628.5 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPC | NM_004628.5 | c.463C>T | p.Arg155Ter | stop_gained | 4/16 | ENST00000285021.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPC | ENST00000285021.12 | c.463C>T | p.Arg155Ter | stop_gained | 4/16 | 1 | NM_004628.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249148Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135180
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461632Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727092
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 29, 2023 | - - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2016 | Variant summary: The XPC c.463C>T (p.Arg155X) variant results in a premature termination codon, predicted to cause a truncated or absent XPC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/120516 (1/60258), which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). Multiple publications cite the variant in affected individuals as homozygotes and compound heterozygotes. In addition, functional studies show the variant of interest to have a deleterious effect on protein function. Therefore, the variant of interest has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg155*) in the XPC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XPC are known to be pathogenic (PMID: 23173980, 25256075). This variant is present in population databases (rs755825264, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 16081512, 23173980, 24218596). This variant is also known as c.567C>T. ClinVar contains an entry for this variant (Variation ID: 496268). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at