rs750218942
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000380.4(XPA):c.390-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,602,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000380.4 splice_acceptor
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
XPA | NM_000380.4 | c.390-1G>C | splice_acceptor_variant | ENST00000375128.5 | NP_000371.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.390-1G>C | splice_acceptor_variant | 1 | NM_000380.4 | ENSP00000364270 | P1 | |||
XPA | ENST00000462523.5 | c.390-1G>C | splice_acceptor_variant, NMD_transcript_variant | 5 | ENSP00000433006 | |||||
XPA | ENST00000496104.1 | n.184-1G>C | splice_acceptor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 242978Hom.: 0 AF XY: 0.00000760 AC XY: 1AN XY: 131606
GnomAD4 exome AF: 0.0000317 AC: 46AN: 1450558Hom.: 0 Cov.: 30 AF XY: 0.0000264 AC XY: 19AN XY: 720582
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Xeroderma pigmentosum group A Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Canonical splice site: predicted to alter splicing and 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).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001235, PM2). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000264684.5). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_000380.3(XPA):c.390-1G>C is a canonical splice variant classified as pathogenic in the context of xeroderma pigmentosum group A. c.390-1G>C has been observed in cases with relevant disease (PMID: 1702221, 7577588). Functional assessments of this variant are available in the literature (PMID: 1702221). c.390-1G>C has been observed in population frequency databases (gnomAD: EAS 0.02%). In summary, NM_000380.3(XPA):c.390-1G>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 26, 2017 | The XPA c.390-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been described as a founder variant in the Japanese population with a carrier frequency of approximately 0.9% (Hirai et al. 2006; Imoto et al. 2013). Across a selection of the available literature, the c.390-1G>C variant has been reported in 24 patients including 20 patients with the variant in a homozygous state and four in a heterozygous state (Satokata et al. 1990; Sun et al. 2015; Choi et al. 2016; Zhou et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00037 in the East Asian population of the Exome Aggregation Consortium. The c.390-1G>C variant affects splicing, creating two abnormally spliced mRNA forms, both of which result in premature truncation of the protein (Satokata et al. 1990). Based on the collective evidence and the potential impact of splice acceptor variants, the c.390-1G>C variant is classified as pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 20, 2020 | Variant summary: XPA c.390-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site and creates/strengthens a cryptic exonic one. Experimental evidence supports these predictions demonstrating the variant results in the production of aberrant mRNA transcripts (Satokata_1990). The variant allele was found at a frequency of 1.2e-05 in 242978 control chromosomes (gnomAD). c.390-1G>C is described in the literature as a founder mutation in the Japanese population and has been reported in multiple individuals affected with Xeroderma Pigmentosum (e.g. Satokata_1990, Hirai_2006, Imoto_2013). These data indicate that the variant is very likely to be associated with disease. Four 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 | Labcorp Genetics (formerly Invitae), Labcorp | Nov 21, 2023 | This sequence change affects an acceptor splice site in intron 3 of the XPA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs750218942, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with xeroderma pigmentosum (PMID: 27607234). It is commonly reported in individuals of Japanese ancestry (PMID: 2234061, 23194742). ClinVar contains an entry for this variant (Variation ID: 264684). Studies have shown that disruption of this splice site results in activation of a cryptic splice site in exon 4 and introduces a premature termination codon (PMID: 1702221). The resulting mRNA is expected to undergo nonsense-mediated decay. 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