chr16-13920167-T-C
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_005236.3(ERCC4):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
ERCC4
NM_005236.3 start_lost
NM_005236.3 start_lost
Scores
6
3
7
Clinical Significance
Conservation
PhyloP100: 1.12
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 Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
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.2T>C | p.Met1? | start_lost | 1/11 | ENST00000311895.8 | |
LOC105371093 | XR_007065000.1 | n.82+6358A>G | intron_variant, non_coding_transcript_variant | ||||
ERCC4 | XM_011522424.4 | c.2T>C | p.Met1? | start_lost | 1/12 | ||
LOC105371093 | XR_007064999.1 | n.82+6358A>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC4 | ENST00000311895.8 | c.2T>C | p.Met1? | start_lost | 1/11 | 1 | NM_005236.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000829 AC: 2AN: 241290Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131970
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1452596Hom.: 0 Cov.: 34 AF XY: 0.00000277 AC XY: 2AN XY: 723100
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2019 | Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease, however a downstream Methionine exists; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PROVEAN
Benign
.;N
REVEL
Benign
Sift
Pathogenic
.;D
Sift4G
Pathogenic
D;D
Polyphen
0.039
.;B
Vest4
MutPred
Gain of glycosylation at M1 (P = 0.0306);Gain of glycosylation at M1 (P = 0.0306);
MVP
ClinPred
D
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