rs752088918
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.566_567delAT(p.Tyr189SerfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004628.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000243 AC: 6AN: 246448Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133816
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1458880Hom.: 0 AF XY: 0.0000152 AC XY: 11AN XY: 725670
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:5
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Xeroderma pigmentosum Pathogenic:1
Variant summary: The c.566_567delAT (p.Tyr189Serfs) variant in XPC gene is a frameshift change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. These predictions were confirmed by Northern blot analysis that has revealed greatly reduced xeroderma pigmentosum complementation group C mRNA as well as reductions in post-ultraviolet survival rate, unscheduled DNA synthesis, global genome DNA repair deficiency and aborted plasmid host cell reactivation (Slor ,2000). The variant is present in the large control population dataset of ExAC at a low frequency 0.00004 (5/113986 chrs tested), exclusively in individuals of European descent (0.000079; 5/63374 chrs tested) which does not exceed the maximal expected frequency of a pathogenic allele (0.0014) in this gene. The variant of interest has been reported homozygously in at least 3 XP-C patients. The c.566_567delAT is cited as Pathogenic by reputable database/diagnostic center. Taken together, the variant was classified as Pathogenic. -
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Tyr189Serfs*10) 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 (rs752088918, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 11121128). It has also been observed to segregate with disease in related individuals. This variant is also known as c.669_670delAT. ClinVar contains an entry for this variant (Variation ID: 258). 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