chr13-102863029-C-A

Variant names:

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.1880C>A(p.Ala627Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,156 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 61 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.966

Publications

8 publications found

Variant links:

COSMIC-nc: COSV63244005

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]

ERCC5 links:

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]

BIVM-ERCC5 links:

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=0.003184855).

BP6

Variant 13-102863029-C-A is Benign according to our data. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-102863029-C-A is described in CliVar as Benign/Likely_benign. Clinvar id is 134192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00338 (514/152278) while in subpopulation AMR AF = 0.0191 (292/15304). AF 95% confidence interval is 0.0173. There are 3 homozygotes in GnomAd4. There are 301 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC5	NM_000123.4 link	c.1880C>A	p.Ala627Glu	missense_variant	Exon 8 of 15	ENST00000652225.2	NP_000114.3	P28715-1
BIVM-ERCC5	NM_001204425.2 link	c.3242C>A	p.Ala1081Glu	missense_variant	Exon 16 of 23		NP_001191354.2	R4GMW8Q59FZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERCC5	ENST00000652225.2 link	c.1880C>A	p.Ala627Glu	missense_variant	Exon 8 of 15		NM_000123.4	ENSP00000498881.2	P28715-1
BIVM-ERCC5	ENST00000639435.1 link	c.3242C>A	p.Ala1081Glu	missense_variant	Exon 18 of 25	5		ENSP00000491742.1	R4GMW8
BIVM-ERCC5	ENST00000639132.1 link	c.2555C>A	p.Ala852Glu	missense_variant	Exon 17 of 24	5		ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

512

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00782

AC:

1965

AN:

251264

AF XY:

0.00603

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0456

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00125

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.000387

Gnomad OTH exome

AF:

0.00621

GnomAD4 exome

AF:

0.00198

AC:

2890

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1263

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.0423

AC:

1894

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26134

East Asian (EAS)

AF:

0.00116

AC:

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0121

AC:

647

AN:

53408

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000123

AC:

137

AN:

1112010

Other (OTH)

AF:

0.00189

AC:

114

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

168

335

503

670

838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00338

AC:

514

AN:

152278

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

301

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41554

American (AMR)

AF:

0.0191

AC:

292

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00290

AC:

AN:

5176

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0127

AC:

135

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000974

Hom.:

Bravo

AF:

0.00459

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00605

AC:

735

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 11, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Xeroderma pigmentosum, group G

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

0.14

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.073

.;.;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.71

T;T;.;T

MetaRNN

Benign

0.0032

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

.;.;.;M

PhyloP100

0.97

PROVEAN

Benign

-1.6

.;.;.;N

REVEL

Benign

0.037

Sift

Benign

0.10

.;.;.;T

Sift4G

Benign

0.50

.;.;.;T

Polyphen

0.65

.;.;.;P

Vest4

0.18

MVP

0.38

MPC

0.28

ClinPred

0.022

GERP RS

3.6

Varity_R

0.13

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over