NM_000123.4:c.640C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000123.4(ERCC5):​c.640C>T​(p.Arg214Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,986 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

3
10
4

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.69

Publications

12 publications found
Variant links:
Genes affected
ERCC5 (HGNC:3437): (ERCC excision repair 5, endonuclease) This gene encodes a single-strand specific DNA endonuclease that makes the 3' incision in DNA excision repair following UV-induced damage. The protein may also function in other cellular processes, including RNA polymerase II transcription, and transcription-coupled DNA repair. Mutations in this gene cause xeroderma pigmentosum complementation group G (XP-G), which is also referred to as xeroderma pigmentosum VII (XP7), a skin disorder characterized by hypersensitivity to UV light and increased susceptibility for skin cancer development following UV exposure. Some patients also develop Cockayne syndrome, which is characterized by severe growth defects, cognitive disability, and cachexia. Read-through transcription exists between this gene and the neighboring upstream BIVM (basic, immunoglobulin-like variable motif containing) gene. [provided by RefSeq, Feb 2011]
BIVM-ERCC5 (HGNC:43690): (BIVM-ERCC5 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BIVM (basic, immunoglobulin-like variable motif containing) and ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5) genes on chromosome 13. The read-through transcript encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009061545).
BP6
Variant 13-102858386-C-T is Benign according to our data. Variant chr13-102858386-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00126 (191/152152) while in subpopulation EAS AF = 0.0164 (85/5170). AF 95% confidence interval is 0.0136. There are 2 homozygotes in GnomAd4. There are 116 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERCC5NM_000123.4 linkc.640C>T p.Arg214Cys missense_variant Exon 6 of 15 ENST00000652225.2 NP_000114.3 P28715-1
BIVM-ERCC5NM_001204425.2 linkc.2002C>T p.Arg668Cys missense_variant Exon 14 of 23 NP_001191354.2 R4GMW8Q59FZ7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERCC5ENST00000652225.2 linkc.640C>T p.Arg214Cys missense_variant Exon 6 of 15 NM_000123.4 ENSP00000498881.2 P28715-1
BIVM-ERCC5ENST00000639435.1 linkc.2002C>T p.Arg668Cys missense_variant Exon 16 of 25 5 ENSP00000491742.1 R4GMW8
BIVM-ERCC5ENST00000639132.1 linkc.1315C>T p.Arg439Cys missense_variant Exon 15 of 24 5 ENSP00000492684.1 A0A1W2PS85

Frequencies

GnomAD3 genomes
AF:
0.00125
AC:
190
AN:
152034
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.0164
Gnomad SAS
AF:
0.00809
Gnomad FIN
AF:
0.00189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00282
AC:
709
AN:
251296
AF XY:
0.00315
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.000636
Gnomad ASJ exome
AF:
0.000595
Gnomad EAS exome
AF:
0.0185
Gnomad FIN exome
AF:
0.00157
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00110
AC:
1613
AN:
1461834
Hom.:
19
Cov.:
31
AF XY:
0.00135
AC XY:
983
AN XY:
727222
show subpopulations
African (AFR)
AF:
0.0000896
AC:
3
AN:
33480
American (AMR)
AF:
0.000626
AC:
28
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.000651
AC:
17
AN:
26132
East Asian (EAS)
AF:
0.0117
AC:
466
AN:
39678
South Asian (SAS)
AF:
0.00932
AC:
804
AN:
86258
European-Finnish (FIN)
AF:
0.00187
AC:
100
AN:
53418
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000854
AC:
95
AN:
1111982
Other (OTH)
AF:
0.00164
AC:
99
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
104
208
313
417
521
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
28
56
84
112
140
<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:
0.00126
AC:
191
AN:
152152
Hom.:
2
Cov.:
32
AF XY:
0.00156
AC XY:
116
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.000289
AC:
12
AN:
41500
American (AMR)
AF:
0.00111
AC:
17
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00115
AC:
4
AN:
3468
East Asian (EAS)
AF:
0.0164
AC:
85
AN:
5170
South Asian (SAS)
AF:
0.00810
AC:
39
AN:
4814
European-Finnish (FIN)
AF:
0.00189
AC:
20
AN:
10576
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000191
AC:
13
AN:
68014
Other (OTH)
AF:
0.000473
AC:
1
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
9
18
28
37
46
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000855
Hom.:
1
Bravo
AF:
0.00117
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00277
AC:
336
Asia WGS
AF:
0.0170
AC:
59
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Sep 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 29, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

BIVM-ERCC5: BP4, BS1, BS2; ERCC5: BP4, BS1, BS2 -

Xeroderma pigmentosum, group G Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Xeroderma pigmentosum, group G;C1851443:Cerebrooculofacioskeletal syndrome 3 Benign:1
Aug 16, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ERCC5-related disorder Benign:1
Mar 29, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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
Uncertain
0.49
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
0.080
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
.;.;.;D;.
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.97
D;D;.;D;D
MetaRNN
Benign
0.0091
T;T;T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.7
.;.;.;M;M
PhyloP100
1.7
PROVEAN
Pathogenic
-6.2
.;.;.;D;D
REVEL
Uncertain
0.35
Sift
Uncertain
0.0010
.;.;.;D;D
Sift4G
Pathogenic
0.0010
.;.;.;D;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.71, 0.84
MVP
0.53
MPC
0.64
ClinPred
0.061
T
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
0.19
Mutation Taster
=90/10
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: rs56255799; hg19: chr13-103510736; COSMIC: COSV100863602; COSMIC: COSV100863602; API