rs121434576
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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
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
ERCC5
NM_000123.4 missense
NM_000123.4 missense
Scores
9
2
1
Clinical Significance
Conservation
PhyloP100: 9.88
Genes affected
ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.878
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC5 | NM_000123.4 | c.2620G>A | p.Ala874Thr | missense_variant | 12/15 | ENST00000652225.2 | |
BIVM-ERCC5 | NM_001204425.2 | c.3982G>A | p.Ala1328Thr | missense_variant | 20/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC5 | ENST00000652225.2 | c.2620G>A | p.Ala874Thr | missense_variant | 12/15 | NM_000123.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251456Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
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GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727234
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Xeroderma pigmentosum, group G Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2002 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 23, 2022 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
Polyphen
1.0
.;.;.;D;.
Vest4
0.62, 0.60
MVP
0.92
MPC
0.54
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at