rs121965088
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.1735C>T(p.Arg579Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000682 in 1,613,826 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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
XPC
NM_004628.5 stop_gained
NM_004628.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.65
Genes affected
XPC (HGNC:12816): (XPC complex subunit, DNA damage recognition and repair factor) The protein encoded by this gene is a key component of the XPC complex, which plays an important role in the early steps of global genome nucleotide excision repair (NER). The encoded protein is important for damage sensing and DNA binding, and shows a preference for single-stranded DNA. Mutations in this gene or some other NER components can result in Xeroderma pigmentosum, a rare autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-14158148-G-A is Pathogenic according to our data. Variant chr3-14158148-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPC | NM_004628.5 | c.1735C>T | p.Arg579Ter | stop_gained | 9/16 | ENST00000285021.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPC | ENST00000285021.12 | c.1735C>T | p.Arg579Ter | stop_gained | 9/16 | 1 | NM_004628.5 | P1 | |
XPC-AS1 | ENST00000627116.2 | n.457-7728G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151996Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249312Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135248
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461712Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727138
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 29, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 12, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | research | Medical Molecular Genetics Department, National Research Center | Dec 01, 2015 | - - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 25, 2020 | Variant summary: XPC c.1735C>T (p.Arg579X) 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. 4/4 computational tools predict no significant impact on normal splicing. However, at least two publications experimental evidence that this variant affects mRNA splicing and results in the deletion of 3 end of exon 8. The variant allele was found at a frequency of 1.2e-05 in 249312 control chromosomes (gnomAD). c.1735C>T has been reported in the literature in individuals affected with Xeroderma Pigmentosum (Chavanne_2000, Gozukara_2001, Masaki_2018). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and results in DNA repair defect (Chavanne_2000, Gozukara_2001). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2023 | This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 10766188, 11511294, 25256075, 29330851). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg579opal. ClinVar contains an entry for this variant (Variation ID: 259). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs121965088, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg579*) 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at