chr9-97675486-T-TA
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000380.4(XPA):c.774_775insT(p.Lys259Ter) 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 (★★). 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
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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.774_775insT | p.Lys259Ter | frameshift_variant | 6/6 | ENST00000375128.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.774_775insT | p.Lys259Ter | frameshift_variant | 6/6 | 1 | NM_000380.4 | P1 | |
XPA | ENST00000485042.1 | n.286_287insT | non_coding_transcript_exon_variant | 2/2 | 3 | ||||
XPA | ENST00000462523.5 | c.*210_*211insT | 3_prime_UTR_variant, NMD_transcript_variant | 7/7 | 5 |
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:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 24, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | 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. 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. 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