chr13-102862938-G-C
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000123.4(ERCC5):āc.1789G>Cā(p.Val597Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,238 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000123.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC5 | NM_000123.4 | c.1789G>C | p.Val597Leu | missense_variant | 8/15 | ENST00000652225.2 | |
BIVM-ERCC5 | NM_001204425.2 | c.3151G>C | p.Val1051Leu | missense_variant | 16/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC5 | ENST00000652225.2 | c.1789G>C | p.Val597Leu | missense_variant | 8/15 | NM_000123.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00151 AC: 230AN: 152228Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00134 AC: 336AN: 251344Hom.: 0 AF XY: 0.00125 AC XY: 170AN XY: 135834
GnomAD4 exome AF: 0.00208 AC: 3040AN: 1461892Hom.: 4 Cov.: 32 AF XY: 0.00202 AC XY: 1469AN XY: 727246
GnomAD4 genome AF: 0.00151 AC: 230AN: 152346Hom.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 94AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 19, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ERCC5 p.Val597Leu variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs4150319), ClinVar (classified as likely benign by DNA and Cytogenetics Diagnostics Unit, Erasmus Medical Center and Genome Diagnostics Laboratory, VU University Medical Center Amsterdam), and LOVD 3.0. The variant was identified in control databases in 348 of 268224 chromosomes at a frequency of 0.001297 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 285 of 118064 chromosomes (freq: 0.002414), European (Finnish) in 30 of 25106 chromosomes (freq: 0.001195), Other in 6 of 6702 chromosomes (freq: 0.000895), Latino in 22 of 35104 chromosomes (freq: 0.000627), African in 4 of 23616 chromosomes (freq: 0.000169) and South Asian in 1 of 30526 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Val597 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | ERCC5: BP4 - |
Xeroderma pigmentosum, group G Uncertain:1Benign:2
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Apr 29, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Cerebrooculofacioskeletal syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 25, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
BIVM-ERCC5-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 30, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 14, 2020 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at