chr2-127259306-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000122.2(ERCC3):​c.2207G>T​(p.Arg736Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. R736S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ERCC3
NM_000122.2 missense

Scores

1
18

Clinical Significance

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

Conservation

PhyloP100: 0.235

Publications

1 publications found
Variant links:
Genes affected
ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
ERCC3 Gene-Disease associations (from GenCC):
  • trichothiodystrophy 2, photosensitive
    Inheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • xeroderma pigmentosum group B
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
  • trichothiodystrophy 1, photosensitive
    Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
  • trichothiodystrophy
    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
  • hereditary breast carcinoma
    Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.11002901).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC3NM_000122.2 linkc.2207G>T p.Arg736Ile missense_variant Exon 14 of 15 ENST00000285398.7 NP_000113.1 P19447

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC3ENST00000285398.7 linkc.2207G>T p.Arg736Ile missense_variant Exon 14 of 15 1 NM_000122.2 ENSP00000285398.2 P19447

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251370
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
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:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000108
AC:
12
AN:
1112010
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
2
3
4
5
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
Cov.:
32
Alfa
AF:
0.0000312
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jun 15, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC3 protein function. ClinVar contains an entry for this variant (Variation ID: 134122). This variant has not been reported in the literature in individuals affected with ERCC3-related conditions. This variant is present in population databases (rs587778276, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 736 of the ERCC3 protein (p.Arg736Ile). -

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
0.30
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.24
T;.
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.86
FATHMM_MKL
Benign
0.58
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.047
D
MetaRNN
Benign
0.11
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.77
N;.
PhyloP100
0.23
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-2.3
N;.
REVEL
Benign
0.059
Sift
Benign
0.16
T;.
Sift4G
Benign
0.11
T;.
Polyphen
0.0090
B;.
Vest4
0.28
MutPred
0.33
Loss of MoRF binding (P = 0.025);.;
MVP
0.52
MPC
0.54
ClinPred
0.082
T
GERP RS
-3.2
Varity_R
0.051
gMVP
0.58
Mutation Taster
=73/27
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: rs587778276; hg19: chr2-128016882; API