chr9-97689600-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000380.4(XPA):c.323G>A(p.Cys108Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,612,820 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C108F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000380.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XPA | NM_000380.4 | c.323G>A | p.Cys108Tyr | missense_variant | 3/6 | ENST00000375128.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XPA | ENST00000375128.5 | c.323G>A | p.Cys108Tyr | missense_variant | 3/6 | 1 | NM_000380.4 | P1 | |
XPA | ENST00000462523.5 | c.323G>A | p.Cys108Tyr | missense_variant, NMD_transcript_variant | 3/7 | 5 | |||
XPA | ENST00000496104.1 | n.184-2339G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460498Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726624
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74496
ClinVar
Submissions by phenotype
Xeroderma pigmentosum group A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 22, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This variant was found once in our laboratory homozygous in a 9-year-old male with photosensitivity and learning problems. A similarly affected sister, who also had ataxia, was also homozygous. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2015 | The C108Y variant in the XPA gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The C108Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C108Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense pathogenic variants in the same residue (C108F) has been reported in the Human Gene Mutation Database in association with xeroderma pigmentosum (Stenson et al., 2014), supporting the functional importance of this region of the protein. The C108Y variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at