rs778543124
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000380.4(XPA):c.772_785del(p.Arg258TyrfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R258R) has been classified as Likely benign.
Frequency
Consequence
NM_000380.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPA | NM_000380.4 | c.772_785del | p.Arg258TyrfsTer5 | frameshift_variant | 6/6 | ENST00000375128.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.772_785del | p.Arg258TyrfsTer5 | frameshift_variant | 6/6 | 1 | NM_000380.4 | P1 | |
XPA | ENST00000485042.1 | n.284_297del | non_coding_transcript_exon_variant | 2/2 | 3 | ||||
XPA | ENST00000462523.5 | c.*208_*221del | 3_prime_UTR_variant, NMD_transcript_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251146Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135726
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461708Hom.: 0 AF XY: 0.0000688 AC XY: 50AN XY: 727136
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Xeroderma pigmentosum group A Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 18, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostic Laboratory, University of Szeged | Jan 05, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
not provided Pathogenic:4
Pathogenic, 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 02, 2024 | This sequence change creates a premature translational stop signal (p.Arg258Tyrfs*5) in the XPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the XPA protein. This variant is present in population databases (rs778543124, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosum (PMID: 31478152). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523608). This variant disrupts the C-terminus of the XPA protein. Other variant(s) that disrupt this region (p.Thr260Ilefs*9) have been observed in individuals with XPA-related conditions (PMID: 20574439). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | XPA: PVS1, PM2, PM3, PP1 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at