rs757958943
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.1243C>T(p.Arg415Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,746 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004628.5 stop_gained
Scores
Clinical Significance
Conservation
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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.1243C>T | p.Arg415Ter | stop_gained | 9/16 | ENST00000285021.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPC | ENST00000285021.12 | c.1243C>T | p.Arg415Ter | stop_gained | 9/16 | 1 | NM_004628.5 | P1 | |
XPC-AS1 | ENST00000627116.2 | n.457-7236G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152066Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249248Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135224
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461680Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727130
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74278
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | StellarGene Technologies Pvt. Ltd. | Jun 19, 2017 | The listed mutation in XPC gene was detected in affected child. The Illumina clinical exome sequencing panel was used and other genes involved in Xeroderma were free of pathogenic/ likely pathogenic variants. The affected child was homozygous for the mutation. The parents were then tested for this variant specifically and confirmed as heterozygous carriers. This variant was reported as pathogenic previously. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000438623, PMID:16081512). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Arg415*) 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 (rs757958943, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 26884178, 29178624). ClinVar contains an entry for this variant (Variation ID: 438623). For these reasons, this variant has been classified as Pathogenic. - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2020 | Variant summary: XPC c.1243C>T (p.Arg415X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 249248 control chromosomes (gnomAD). c.1243C>T has been reported in the literature in multiple individuals affected with Xeroderma pigmentosum (Tamhankar_2015, Fassihi_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at