chr16-13920199-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005236.3(ERCC4):āc.34A>Gā(p.Met12Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,607,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.000013 ( 0 hom. )
Consequence
ERCC4
NM_005236.3 missense
NM_005236.3 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 7.98
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC4 | NM_005236.3 | c.34A>G | p.Met12Val | missense_variant | 1/11 | ENST00000311895.8 | |
LOC105371093 | XR_007065000.1 | n.82+6326T>C | intron_variant, non_coding_transcript_variant | ||||
ERCC4 | XM_011522424.4 | c.34A>G | p.Met12Val | missense_variant | 1/12 | ||
LOC105371093 | XR_007064999.1 | n.82+6326T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC4 | ENST00000311895.8 | c.34A>G | p.Met12Val | missense_variant | 1/11 | 1 | NM_005236.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000246 AC: 6AN: 243986Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 132992
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GnomAD4 exome AF: 0.0000131 AC: 19AN: 1454792Hom.: 0 Cov.: 35 AF XY: 0.0000166 AC XY: 12AN XY: 724092
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. This variant is present in population databases (rs750358005, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the ERCC4 protein (p.Met12Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N
REVEL
Benign
Sift
Uncertain
.;D
Sift4G
Benign
T;T
Polyphen
0.073
.;B
Vest4
MutPred
Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);
MVP
MPC
0.082
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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