chr16-13948186-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005236.3(ERCC4):​c.2590C>T​(p.Arg864Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R864H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 1.57

Publications

3 publications found
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]
ERCC4 Gene-Disease associations (from GenCC):
  • xeroderma pigmentosum group F
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
  • Fanconi anemia complementation group Q
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • XFE progeroid syndrome
    Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • xeroderma pigmentosum
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • xeroderma pigmentosum-Cockayne syndrome complex
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18589684).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC4NM_005236.3 linkc.2590C>T p.Arg864Cys missense_variant Exon 11 of 11 ENST00000311895.8 NP_005227.1 Q92889-1A0A1W1GSK9
ERCC4XM_011522424.4 linkc.2728C>T p.Arg910Cys missense_variant Exon 12 of 12 XP_011520726.1 A0A804HKF9
ERCC4XM_047433774.1 linkc.1801C>T p.Arg601Cys missense_variant Exon 8 of 8 XP_047289730.1
ERCC4XM_011522427.2 linkc.1240C>T p.Arg414Cys missense_variant Exon 6 of 6 XP_011520729.1 B4DXD8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC4ENST00000311895.8 linkc.2590C>T p.Arg864Cys missense_variant Exon 11 of 11 1 NM_005236.3 ENSP00000310520.7 Q92889-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251424
AF XY:
0.00000736
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461888
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
727244
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000719
AC:
8
AN:
1112008
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.454
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41410
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other: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
Nov 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 864 of the ERCC4 protein (p.Arg864Cys). This variant is present in population databases (rs587778284, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 134139). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ERCC4 protein function with a positive predictive value of 80%. 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. -

not specified Other:1
Sep 19, 2013
ITMI
Significance:not provided
Review Status:no classification provided
Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Benign
-0.071
Eigen_PC
Benign
0.038
FATHMM_MKL
Benign
0.31
N
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M
PhyloP100
1.6
PrimateAI
Benign
0.23
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Benign
0.12
Sift
Uncertain
0.027
D
Sift4G
Benign
0.13
T
Polyphen
0.028
B
Vest4
0.22
MutPred
0.54
Loss of MoRF binding (P = 0.0056);
MVP
0.45
MPC
0.11
ClinPred
0.81
D
GERP RS
5.0
Varity_R
0.24
gMVP
0.45
Mutation Taster
=71/29
polymorphism

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

Other links and lift over

dbSNP: rs587778284; hg19: chr16-14042043; COSMIC: COSV61311071; COSMIC: COSV61311071; API