rs1799802
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2
The NM_005236.3(ERCC4):c.1135C>T(p.Pro379Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,611,848 control chromosomes in the GnomAD database, including 33 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 0.0045 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0057 ( 32 hom. )
Consequence
ERCC4
NM_005236.3 missense
NM_005236.3 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 7.57
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.
PP3
?
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.011538804).
BS2
?
High Homozygotes in GnomAdExome4 at 32 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC4 | NM_005236.3 | c.1135C>T | p.Pro379Ser | missense_variant | 7/11 | ENST00000311895.8 | |
ERCC4 | XM_011522424.4 | c.1273C>T | p.Pro425Ser | missense_variant | 8/12 | ||
ERCC4 | XM_047433774.1 | c.346C>T | p.Pro116Ser | missense_variant | 4/8 | ||
ERCC4 | XM_011522427.2 | c.-216C>T | 5_prime_UTR_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC4 | ENST00000311895.8 | c.1135C>T | p.Pro379Ser | missense_variant | 7/11 | 1 | NM_005236.3 | P1 | |
ENST00000570663.1 | n.219+1193G>A | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00451 AC: 680AN: 150838Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00400 AC: 1003AN: 250774Hom.: 6 AF XY: 0.00416 AC XY: 564AN XY: 135640
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GnomAD4 exome AF: 0.00567 AC: 8286AN: 1460892Hom.: 32 Cov.: 29 AF XY: 0.00548 AC XY: 3981AN XY: 726776
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GnomAD4 genome ? AF: 0.00450 AC: 680AN: 150956Hom.: 1 Cov.: 33 AF XY: 0.00470 AC XY: 346AN XY: 73614
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:8Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 06, 2015 | - - |
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, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ENSG00000262732: BS2; ERCC4: BS2 - |
not specified Benign:2Other:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 08, 2022 | Variant summary: ERCC4 c.1135C>T (p.Pro379Ser) 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 0.004 in 250774 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 20 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 benign. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2), likely benign (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 24, 2021 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Xeroderma pigmentosum Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 11, 2020 | - - |
ERCC4-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 25, 2019 | 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). - |
Xeroderma pigmentosum, group F Benign:1
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Aug 23, 2022 | This variant has been reported in the literature in the compound heterozygous and homozygous states in at least 3 individuals with mild xeroderma pigmentosum (Ahmad 2010 PMID:20221251; Fassihi 2016 PMID:26884178). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.7% [463/67788], including in 7 total homozygotes; https://gnomad.broadinstitute.org/variant/16-13934224-C-T?dataset=gnomad_r3), and is present in ClinVar (Variation ID:134148). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies have shown a mildly deleterious effect of this variant on some aspects of protein function, while minimal to no effect on other aspects (Ahmad 2010 PMID:20221251; Sabatella 2018 PMID:30165384). However, these studies may not accurately represent in vivo biological function. This variant may confer a slight increase in the risk for sunburn (OR: 1.31, 95% CI [1.257, 1.431]) (Backman 2021 PMID:34662886). In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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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