chr16-13920199-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005236.3(ERCC4):ā€‹c.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

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98
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]

Genome browser will be placed here

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
ERCC4NM_005236.3 linkuse as main transcriptc.34A>G p.Met12Val missense_variant 1/11 ENST00000311895.8
LOC105371093XR_007065000.1 linkuse as main transcriptn.82+6326T>C intron_variant, non_coding_transcript_variant
ERCC4XM_011522424.4 linkuse as main transcriptc.34A>G p.Met12Val missense_variant 1/12
LOC105371093XR_007064999.1 linkuse as main transcriptn.82+6326T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERCC4ENST00000311895.8 linkuse as main transcriptc.34A>G p.Met12Val missense_variant 1/111 NM_005236.3 P1Q92889-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000246
AC:
6
AN:
243986
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
132992
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000546
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000894
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000131
AC:
19
AN:
1454792
Hom.:
0
Cov.:
35
AF XY:
0.0000166
AC XY:
12
AN XY:
724092
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingInvitaeFeb 22, 2022Algorithms 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.15
.;T
Eigen
Benign
-0.087
Eigen_PC
Benign
0.053
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.60
T;T
M_CAP
Uncertain
0.087
D
MetaRNN
Uncertain
0.61
D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.95
.;N
REVEL
Benign
0.19
Sift
Uncertain
0.014
.;D
Sift4G
Benign
0.20
T;T
Polyphen
0.073
.;B
Vest4
0.68
MutPred
0.31
Loss of disorder (P = 0.0982);Loss of disorder (P = 0.0982);
MVP
0.88
MPC
0.082
ClinPred
0.80
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.82
gMVP
0.51

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: rs750358005; hg19: chr16-14014056; API