chr16-13920167-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_005236.3(ERCC4):ā€‹c.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

Scores

6
3
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12
Variant links:
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
ERCC4NM_005236.3 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/11 ENST00000311895.8
LOC105371093XR_007065000.1 linkuse as main transcriptn.82+6358A>G intron_variant, non_coding_transcript_variant
ERCC4XM_011522424.4 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/12
LOC105371093XR_007064999.1 linkuse as main transcriptn.82+6358A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERCC4ENST00000311895.8 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/111 NM_005236.3 P1Q92889-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000829
AC:
2
AN:
241290
Hom.:
0
AF XY:
0.0000152
AC XY:
2
AN XY:
131970
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000903
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1452596
Hom.:
0
Cov.:
34
AF XY:
0.00000277
AC XY:
2
AN XY:
723100
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000284
Hom.:
0
Bravo
AF:
0.00000378

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 submitterclinical testingGeneDxSep 30, 2019Initiation 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.090
.;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.083
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Benign
-0.83
T
MutationTaster
Benign
1.0
N;N
PROVEAN
Benign
-0.11
.;N
REVEL
Benign
0.28
Sift
Pathogenic
0.0
.;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.039
.;B
Vest4
0.51
MutPred
0.97
Gain of glycosylation at M1 (P = 0.0306);Gain of glycosylation at M1 (P = 0.0306);
MVP
0.91
ClinPred
0.99
D
GERP RS
4.0
Varity_R
0.87
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778859873; hg19: chr16-14014024; API