3-14158238-GCA-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004628.5(XPC):c.1643_1644delTG(p.Val548AlafsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000105 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as 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: 0.0000329 AC: 5AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249358Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135252
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461710Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727136
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74282
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group C Pathogenic:7Other:1
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The XPC c.1643_1644delTG p.(Val548AlafsTer25) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is reported in the literature to be a founder variant in the North African population and has been reported in a homozygous state in at least 84 individuals with a phenotype consistent with xeroderma pigmentosum (Soufir et al. 2010; Sehnaji et al. 2013; Bensenouci et al. 2016). The highest frequency of this allele in the Genome Aggregation database is 0.000116 in the Admixed American population (version 2.1.1). Based on the available evidence the c.1643_1644delTG p.(Val548AlafsTer25) variant is classified as pathogenic for xeroderma pigmentosum. -
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Frameshift: 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: VCV000000262, PMID:8298653). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:5
This sequence change creates a premature translational stop signal (p.Val548Alafs*25) 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 (rs754532049, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 20054342, 23143338, 27413738). It is commonly reported in individuals of North African ancestry (PMID: 20054342, 23143338, 27413738). ClinVar contains an entry for this variant (Variation ID: 262). For these reasons, this variant has been classified as Pathogenic. -
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XPC: PS4, PVS1:Strong, PM2 -
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Xeroderma pigmentosum Pathogenic:1
Variant summary: The XPC c.1643_1644delTG (p.Val548AlafsX25) 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. One in silico tool predicts a damaging outcome for this variant. Functional studies showed absence of XPC protein expression in lymphoblasts from XP patients and reduced post-UV unscheduled DNA synthesis (Khan_2006). This variant was found in 5/246258 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic XPC variant (0.0014142). This variant is considered a founder mutation and is reported in 87% of XP-C cases from North Africa (Bensenouci_2016, El-Harith_2012, Khan_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
See cases Pathogenic:1
ACMG classification criteria: PVS1, PS4, PM2 -
XPC-related disorder Pathogenic:1
The XPC c.1643_1644delTG variant is predicted to result in a frameshift and premature protein termination (p.Val548Alafs*25). This variant has been frequently reported in the homozygous or compound heterozygous state in individuals with xeroderma pigmentosum group C and it is considered a founder variant in North African populations (see for example, Mahindra et al. 2008. PubMed ID: 19119101; Ben Rakaya et al. 2009. PubMed ID: 19478817; Soufir et al. 2010. PubMed ID: 20054342; Santiago et al. 2020. PubMed ID: 32239545; Rabie et al. 2021. PubMed ID: 33672602). In vitro functional studies also support its pathogenicity (Schäfer et al. 2013. PubMed ID: 23173980). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in XPC are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at