13-102868199-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000123.4(ERCC5):c.2620G>A(p.Ala874Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,042 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 Uncertain significance (★★).
Frequency
Consequence
NM_000123.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC5 | ENST00000652225.2 | c.2620G>A | p.Ala874Thr | missense_variant | Exon 12 of 15 | NM_000123.4 | ENSP00000498881.2 | |||
BIVM-ERCC5 | ENST00000639435.1 | c.3982G>A | p.Ala1328Thr | missense_variant | Exon 22 of 25 | 5 | ENSP00000491742.1 | |||
BIVM-ERCC5 | ENST00000639132.1 | c.3295G>A | p.Ala1099Thr | missense_variant | Exon 21 of 24 | 5 | ENSP00000492684.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251456Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727234
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74346
ClinVar
Submissions by phenotype
Xeroderma pigmentosum, group G Pathogenic:1Uncertain:1
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The ERCC5 c.2620G>A (p.Ala874Thr) missense variant has been reported in a single study in which it was found in a compound heterozygous state with a stop-gained variant in one patient with a mild phenotype belonging to the xeroderma pigmentosum (XP) complementation group G (Emmert et al. 2002). The p.Ala874Thr variant was absent from 104 controls (Emmert et al. 2002) and is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Functional studies of the variant in patient fibroblasts showed a marked reduction in post-UV cell survival and DNA repair compared to wild type cells but nearly normal levels of mRNA expression. The variant protein was also shown to have residual ability to complement XP group G cells, consistent with the mild phenotype (Emmert et al. 2002). The p.Ala874Thr variant is located in the highly conserved I-region that is thought to be part of the active site of the enzyme. Based on the evidence, the p.Ala874Thr variant is considered to be of unknown significance but suspicious for pathogenicity for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not specified Uncertain:1
Variant summary: ERCC5 c.2620G>A (p.Ala874Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251456 control chromosomes (gnomAD). c.2620G>A has been reported in the literature in a compound heterozygous individual who carried a truncating variant in trans, and was affected with a milder phenotype (i.e. sun sensitivity but no neurological abnormalities) of Xeroderma Pigmentosum (Emmert_2002). These data do not allow clear conclusions about variant significance. However, publications also reported experimental evidence evaluating an impact on protein function, and demonstrated markedly decreased but significant residual activity for the variant protein (Emmert_2002, Tsutakawa_2020), which is consistent with the milder phenotype. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance (but suspicious for pathogenicity). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Inborn genetic diseases Uncertain:1
The c.2620G>A (p.A874T) alteration is located in exon 12 (coding exon 12) of the ERCC5 gene. This alteration results from a G to A substitution at nucleotide position 2620, causing the alanine (A) at amino acid position 874 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at