rs3176750
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000380.4(XPA):āc.754C>Gā(p.Leu252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,834 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L252L) has been classified as Likely benign.
Frequency
Consequence
NM_000380.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPA | NM_000380.4 | c.754C>G | p.Leu252Val | missense_variant | 6/6 | ENST00000375128.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.754C>G | p.Leu252Val | missense_variant | 6/6 | 1 | NM_000380.4 | P1 | |
XPA | ENST00000485042.1 | n.266C>G | non_coding_transcript_exon_variant | 2/2 | 3 | ||||
XPA | ENST00000462523.5 | c.*190C>G | 3_prime_UTR_variant, NMD_transcript_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00985 AC: 1497AN: 151966Hom.: 26 Cov.: 33
GnomAD3 exomes AF: 0.00286 AC: 718AN: 251250Hom.: 6 AF XY: 0.00210 AC XY: 285AN XY: 135796
GnomAD4 exome AF: 0.000997 AC: 1458AN: 1461750Hom.: 12 Cov.: 31 AF XY: 0.000869 AC XY: 632AN XY: 727172
GnomAD4 genome ? AF: 0.00986 AC: 1499AN: 152084Hom.: 25 Cov.: 33 AF XY: 0.00943 AC XY: 701AN XY: 74322
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The XPA p.Leu252Val variant was identified in dbSNP (ID: rs3176750), ClinVar (classified as likely benign for Xeroderma Pigmentosum by Illumina); the variant was not identified in Cosmic or LOVD 3.0. The variant was also identified in control databases in 1001 of 282596 chromosomes (16 homozygous) at a frequency of 0.003542 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 859 of 24952 chromosomes (freq: 0.03443), Latino in 101 of 35382 chromosomes (freq: 0.002855), Other in 17 of 7216 chromosomes (freq: 0.002356), European (non-Finnish) in 23 of 129016 chromosomes (freq: 0.000178), South Asian in 1 of 30610 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Leu252 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Xeroderma pigmentosum group A Benign:2
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at