rs574826021
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000123.4(ERCC5):c.2890C>T(p.Arg964Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,034 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 2 hom. )
Consequence
ERCC5
NM_000123.4 missense
NM_000123.4 missense
Scores
1
7
4
Clinical Significance
Conservation
PhyloP100: 3.50
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.012886673).
BP6
?
Variant 13-102873269-C-T is Benign according to our data. Variant chr13-102873269-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134165.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, not_provided=1}.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000131 (20/152240) while in subpopulation SAS AF= 0.00353 (17/4816). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC5 | NM_000123.4 | c.2890C>T | p.Arg964Trp | missense_variant | 14/15 | ENST00000652225.2 | |
BIVM-ERCC5 | NM_001204425.2 | c.4252C>T | p.Arg1418Trp | missense_variant | 22/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC5 | ENST00000652225.2 | c.2890C>T | p.Arg964Trp | missense_variant | 14/15 | NM_000123.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152122Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000497 AC: 125AN: 251442Hom.: 1 AF XY: 0.000714 AC XY: 97AN XY: 135890
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GnomAD4 exome AF: 0.000248 AC: 362AN: 1461794Hom.: 2 Cov.: 30 AF XY: 0.000348 AC XY: 253AN XY: 727208
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GnomAD4 genome ? AF: 0.000131 AC: 20AN: 152240Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74442
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24728327, 28991257, 26344056) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 26, 2021 | - - |
Xeroderma pigmentosum, group G Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.52, 0.57
MutPred
0.54
.;.;.;Gain of catalytic residue at E960 (P = 0.0691);.;
MVP
0.91
MPC
0.56
ClinPred
T
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