rs104894132
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000380.4(XPA):c.682C>T(p.Arg228Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00017 in 1,613,522 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. R228R) has been classified as Likely benign.
Frequency
Consequence
NM_000380.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPA | NM_000380.4 | c.682C>T | p.Arg228Ter | stop_gained | 6/6 | ENST00000375128.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.682C>T | p.Arg228Ter | stop_gained | 6/6 | 1 | NM_000380.4 | P1 | |
XPA | ENST00000485042.1 | n.194C>T | non_coding_transcript_exon_variant | 2/2 | 3 | ||||
XPA | ENST00000462523.5 | c.*118C>T | 3_prime_UTR_variant, NMD_transcript_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000310 AC: 47AN: 151846Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000299 AC: 75AN: 250924Hom.: 0 AF XY: 0.000265 AC XY: 36AN XY: 135594
GnomAD4 exome AF: 0.000155 AC: 227AN: 1461676Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102AN XY: 727134
GnomAD4 genome ? AF: 0.000310 AC: 47AN: 151846Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 30AN XY: 74130
ClinVar
Submissions by phenotype
Xeroderma pigmentosum group A Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
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 protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000000995, PMID:8105686, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000337, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1995 | - - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 03, 2018 | Variant summary: XPA c.682C>T (p.Arg228X) 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. The variant allele was found at a frequency of 0.00034 in 276474 control chromosomes (gnomAD). c.682C>T has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (Messaoud_2010, Kindil_2017). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (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 | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Arg228*) in the XPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the XPA protein. This variant is present in population databases (rs104894132, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with xeroderma pigmentosum (PMID: 8105686, 20534089, 26743599, 27413738, 27607234, 29208038). It is commonly reported in individuals of North African ancestry (PMID: 8105686, 20534089, 26743599, 27413738, 27607234, 29208038). ClinVar contains an entry for this variant (Variation ID: 995). 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