NM_000380.4:c.774dupT
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000380.4(XPA):c.774dupT(p.Lys259fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000380.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.774dupT | p.Lys259fs | frameshift_variant | Exon 6 of 6 | 1 | NM_000380.4 | ENSP00000364270.5 | ||
XPA | ENST00000462523.5 | n.*210dupT | non_coding_transcript_exon_variant | Exon 7 of 7 | 5 | ENSP00000433006.1 | ||||
XPA | ENST00000485042.1 | n.286dupT | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 | |||||
XPA | ENST00000462523.5 | n.*210dupT | 3_prime_UTR_variant | Exon 7 of 7 | 5 | ENSP00000433006.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251188Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135750
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727064
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Xeroderma pigmentosum group A Pathogenic:2
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not provided Pathogenic:1
This variant disrupts a region of the XPA protein in which other variant(s) (p.Thr260Ilefs*9) have been determined to be pathogenic (PMID: 20574439). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 558017). This variant has not been reported in the literature in individuals affected with XPA-related conditions. This variant is present in population databases (rs752573039, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Lys259*) in the XPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the XPA protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at