chr16-13920167-T-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_005236.3(ERCC4):c.2T>C(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 (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ERCC4
NM_005236.3 start_lost
NM_005236.3 start_lost
Scores
5
3
4
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
?
Cov.:
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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?
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
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
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