rs144725456
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000380.4(XPA):āc.731A>Gā(p.His244Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,613,928 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000072 ( 0 hom., cov: 33)
Exomes š: 0.00012 ( 0 hom. )
Consequence
XPA
NM_000380.4 missense
NM_000380.4 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 7.07
Genes affected
XPA (HGNC:12814): (XPA, DNA damage recognition and repair factor) This gene encodes a zinc finger protein plays a central role in nucleotide excision repair (NER), a specialized type of DNA repair. NER is responsible for repair of UV radiation-induced photoproducts and DNA adducts induced by chemical carcinogens and chemotherapeutic drugs. The encoded protein interacts with DNA and several NER proteins, acting as a scaffold to assemble the NER incision complex at sites of DNA damage. Mutations in this gene cause Xeroderma pigmentosum complementation group A (XP-A), an autosomal recessive skin disorder featuring hypersensitivity to sunlight and increased risk for skin cancer. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.972
PP5
?
Variant 9-97675530-T-C is Pathogenic according to our data. Variant chr9-97675530-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 364088.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=1}. Variant chr9-97675530-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPA | NM_000380.4 | c.731A>G | p.His244Arg | missense_variant | 6/6 | ENST00000375128.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.731A>G | p.His244Arg | missense_variant | 6/6 | 1 | NM_000380.4 | P1 | |
XPA | ENST00000485042.1 | n.243A>G | non_coding_transcript_exon_variant | 2/2 | 3 | ||||
XPA | ENST00000462523.5 | c.*167A>G | 3_prime_UTR_variant, NMD_transcript_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000127 AC: 32AN: 251262Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135804
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GnomAD4 exome AF: 0.000118 AC: 172AN: 1461774Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 75AN XY: 727190
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Xeroderma pigmentosum group A Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 03, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The XPA c.731A>G (p.His244Arg) variant is a missense variant that has been reported in at least one study, in which it was found in a compound heterozygous state in one individual with xeroderma pigmentosum (Satokata et al. 1992). Control data are unavailable for this variant, which is reported at a frequency of 0.00045 in the European (Finnish) population of the Exome Aggregation Consortium. In vitro studies using patient-derived cell lines found the p.His244Arg variant to have reduced ultraviolet resistance while maintaining expression levels similar to wildtype (Satokata et al. 1992; Kobayashi et al. 1998). The evidence for this variant is limited. Therefore, the p.His244Arg variant is classified as a variant of unknown significance but suspicious for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 244 of the XPA protein (p.His244Arg). This variant is present in population databases (rs144725456, gnomAD 0.02%). This missense change has been observed in individual(s) with xeroderma pigmentosum (PMID: 1372103, 34234304). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 364088). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt XPA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects XPA function (PMID: 9753735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2023 | Variant summary: XPA c.731A>G (p.His244Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251262 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in XPA causing Xeroderma Pigmentosum (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.731A>G has been reported in the literature in individuals affected with Xeroderma Pigmentosum or related disorder (Satokata_1992, Benkirane_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The results showed that cells with H244R had partially reduced UV resistance (Satokata_1992, Kobayashi_1998). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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