16-13926630-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_005236.3(ERCC4):​c.458G>T​(p.Arg153Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ERCC4
NM_005236.3 missense

Scores

14
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-13926630-G-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC4NM_005236.3 linkc.458G>T p.Arg153Leu missense_variant Exon 3 of 11 ENST00000311895.8 NP_005227.1 Q92889-1A0A1W1GSK9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC4ENST00000311895.8 linkc.458G>T p.Arg153Leu missense_variant Exon 3 of 11 1 NM_005236.3 ENSP00000310520.7 Q92889-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251460
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Pathogenic
3.8
H;H
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-6.7
.;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
.;D
Vest4
0.92
MutPred
0.59
Gain of catalytic residue at Q154 (P = 0.0317);Gain of catalytic residue at Q154 (P = 0.0317);
MVP
0.93
MPC
0.49
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.82
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs121913050; hg19: chr16-14020487; COSMIC: COSV100318638; COSMIC: COSV100318638; API