rs374186605
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_005236.3(ERCC4):āc.2545C>Gā(p.Gln849Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000052 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000085 ( 0 hom., cov: 32)
Exomes š: 0.000049 ( 0 hom. )
Consequence
ERCC4
NM_005236.3 missense
NM_005236.3 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 5.63
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 Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10146201).
BP6
Variant 16-13948141-C-G is Benign according to our data. Variant chr16-13948141-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134137.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Benign=2, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC4 | NM_005236.3 | c.2545C>G | p.Gln849Glu | missense_variant | 11/11 | ENST00000311895.8 | NP_005227.1 | |
ERCC4 | XM_011522424.4 | c.2683C>G | p.Gln895Glu | missense_variant | 12/12 | XP_011520726.1 | ||
ERCC4 | XM_047433774.1 | c.1756C>G | p.Gln586Glu | missense_variant | 8/8 | XP_047289730.1 | ||
ERCC4 | XM_011522427.2 | c.1195C>G | p.Gln399Glu | missense_variant | 6/6 | XP_011520729.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERCC4 | ENST00000311895.8 | c.2545C>G | p.Gln849Glu | missense_variant | 11/11 | 1 | NM_005236.3 | ENSP00000310520 | P1 | |
ERCC4 | ENST00000682617.1 | c.2683C>G | p.Gln895Glu | missense_variant | 12/12 | ENSP00000507912 | ||||
ERCC4 | ENST00000389138.7 | n.1822C>G | non_coding_transcript_exon_variant | 6/6 | 2 | |||||
ERCC4 | ENST00000683962.1 | c.*2239C>G | 3_prime_UTR_variant, NMD_transcript_variant | 12/12 | ENSP00000506854 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251414Hom.: 1 AF XY: 0.0000442 AC XY: 6AN XY: 135874
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GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32AN XY: 727244
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GnomAD4 genome AF: 0.0000854 AC: 13AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Xeroderma pigmentosum Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 24, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2022 | The c.2545C>G (p.Q849E) alteration is located in exon 11 (coding exon 11) of the ERCC4 gene. This alteration results from a C to G substitution at nucleotide position 2545, causing the glutamine (Q) at amino acid position 849 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 13, 2024 | - - |
Fanconi anemia complementation group Q Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to glutamic acid (exon 11). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (23 heterozygotes, 1 homozygote). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Gln849Leu); 9 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (Rad1 superfamily; NCBI)(N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals (ClinVar). (B) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is bialleic. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Xeroderma pigmentosum, group F Benign:1
Likely benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
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
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of ubiquitination at K854 (P = 0.0543);
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