rs1800069
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_005236.3(ERCC4):āc.2117T>Cā(p.Ile706Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,150 control chromosomes in the GnomAD database, including 8 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: š 0.0018 ( 0 hom., cov: 32)
Exomes š: 0.0025 ( 8 hom. )
Consequence
ERCC4
NM_005236.3 missense
NM_005236.3 missense
Scores
6
7
6
Clinical Significance
Conservation
PhyloP100: 7.45
Genes affected
ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.19945452).
BP6
Variant 16-13947713-T-C is Benign according to our data. Variant chr16-13947713-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134142.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5, not_provided=1, Benign=2}.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC4 | NM_005236.3 | c.2117T>C | p.Ile706Thr | missense_variant | 11/11 | ENST00000311895.8 | NP_005227.1 | |
ERCC4 | XM_011522424.4 | c.2255T>C | p.Ile752Thr | missense_variant | 12/12 | XP_011520726.1 | ||
ERCC4 | XM_047433774.1 | c.1328T>C | p.Ile443Thr | missense_variant | 8/8 | XP_047289730.1 | ||
ERCC4 | XM_011522427.2 | c.767T>C | p.Ile256Thr | missense_variant | 6/6 | XP_011520729.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC4 | ENST00000311895.8 | c.2117T>C | p.Ile706Thr | missense_variant | 11/11 | 1 | NM_005236.3 | ENSP00000310520.7 |
Frequencies
GnomAD3 genomes AF: 0.00176 AC: 268AN: 152258Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00147 AC: 369AN: 251444Hom.: 1 AF XY: 0.00137 AC XY: 186AN XY: 135896
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GnomAD4 exome AF: 0.00250 AC: 3652AN: 1461892Hom.: 8 Cov.: 32 AF XY: 0.00234 AC XY: 1703AN XY: 727248
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GnomAD4 genome AF: 0.00176 AC: 268AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.00173 AC XY: 129AN XY: 74388
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1Other:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 26, 2022 | Variant summary: ERCC4 c.2117T>C (p.Ile706Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 05, 2016 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ERCC4 p.Ile706Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs1800069), LOVD 3.0 and ClinVar (classified as uncertain significance by Genetic Services Laboratory, University of Chicage, and as likely benign by Invitae). The variant was identified in control databases in 366 of 268308 chromosomes (1 homozygous) at a frequency of 0.001364 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 283 of 118142 chromosomes (freq: 0.002395), Other in 12 of 6702 chromosomes (freq: 0.001791), Latino in 50 of 35108 chromosomes (freq: 0.001424), European (Finnish) in 11 of 25108 chromosomes (freq: 0.000438), African in 9 of 23614 chromosomes (freq: 0.000381) and Ashkenazi Jewish in 1 of 9858 chromosomes (freq: 0.000101), but was not observed in the East Asian or South Asian populations. The p.Ile706 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Fanconi anemia complementation group Q Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 14, 2024 | The ERCC4 c.2117T>C (p.Ile706Thr) missense change has a maximum subpopulation frequency of 0.31% in gnomAD v4.0.0 with 8 homozygotes (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ataxia (PMID: 31692161), head and neck squamous cell carcinoma (PMID: 28678401), and pancreatic ductal adenocarcinoma (PMID: 28767289). To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, this variant meets criteria to be classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 03, 2021 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
XFE progeroid syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 09, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Xeroderma pigmentosum, group F Uncertain:1
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Xeroderma pigmentosum Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 29, 2020 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
ERCC4-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 10, 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
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