NM_000123.4:c.1586G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000123.4(ERCC5):c.1586G>C(p.Cys529Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,614,202 control chromosomes in the GnomAD database, including 1,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. C529C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.044 ( 161 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1251 hom. )

Consequence

ERCC5
NM_000123.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:9O:1

Conservation

PhyloP100: 0.247

Publications

51 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]

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=0.0019605458).

BP6

Variant 13-102862735-G-C is Benign according to our data. Variant chr13-102862735-G-C is described in ClinVar as Benign. ClinVar VariationId is 129010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000123.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC5	NM_000123.4	MANE Select	c.1586G>C	p.Cys529Ser	missense	Exon 8 of 15	NP_000114.3
	BIVM-ERCC5	NM_001204425.2		c.2948G>C	p.Cys983Ser	missense	Exon 16 of 23	NP_001191354.2	R4GMW8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC5	ENST00000652225.2	MANE Select	c.1586G>C	p.Cys529Ser	missense	Exon 8 of 15	ENSP00000498881.2	P28715-1
BIVM-ERCC5	ENST00000639435.1	TSL:5	c.2948G>C	p.Cys983Ser	missense	Exon 18 of 25	ENSP00000491742.1	R4GMW8
BIVM-ERCC5	ENST00000639132.1	TSL:5	c.2261G>C	p.Cys754Ser	missense	Exon 17 of 24	ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes

AF:

0.0437

AC:

6648

AN:

152204

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0418

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.0450

Gnomad SAS

AF:

0.0471

Gnomad FIN

AF:

0.0683

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0446

Gnomad OTH

AF:

0.0531

GnomAD2 exomes

AF:

0.0426

AC:

10707

AN:

251362

AF XY:

0.0434

show subpopulations

Gnomad AFR exome

AF:

0.0407

Gnomad AMR exome

AF:

0.0217

Gnomad ASJ exome

AF:

0.0349

Gnomad EAS exome

AF:

0.0455

Gnomad FIN exome

AF:

0.0694

Gnomad NFE exome

AF:

0.0434

Gnomad OTH exome

AF:

0.0463

GnomAD4 exome

AF:

0.0398

AC:

58133

AN:

1461880

Hom.:

1251

Cov.:

AF XY:

0.0401

AC XY:

29180

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0442

AC:

1480

AN:

33480

American (AMR)

AF:

0.0231

AC:

1031

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

965

AN:

26136

East Asian (EAS)

AF:

0.0517

AC:

2053

AN:

39700

South Asian (SAS)

AF:

0.0443

AC:

3821

AN:

86256

European-Finnish (FIN)

AF:

0.0667

AC:

3562

AN:

53418

Middle Eastern (MID)

AF:

0.0704

AC:

406

AN:

5768

European-Non Finnish (NFE)

AF:

0.0380

AC:

42278

AN:

1112004

Other (OTH)

AF:

0.0420

AC:

2537

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

4408

8816

13225

17633

22041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1530

3060

4590

6120

7650

<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:

0.0437

AC:

6656

AN:

152322

Hom.:

161

Cov.:

AF XY:

0.0444

AC XY:

3307

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0419

AC:

1743

AN:

41582

American (AMR)

AF:

0.0297

AC:

454

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3472

East Asian (EAS)

AF:

0.0451

AC:

234

AN:

5184

South Asian (SAS)

AF:

0.0476

AC:

230

AN:

4832

European-Finnish (FIN)

AF:

0.0683

AC:

725

AN:

10612

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0446

AC:

3031

AN:

68022

Other (OTH)

AF:

0.0521

AC:

110

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

341

682

1024

1365

1706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0430

Hom.:

123

Bravo

AF:

0.0395

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.0433

AC:

191

ESP6500EA

AF:

0.0431

AC:

371

ExAC

AF:

0.0441

AC:

5357

Asia WGS

AF:

0.0460

AC:

160

AN:

3478

EpiCase

AF:

0.0400

EpiControl

AF:

0.0406

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Xeroderma pigmentosum, group G (4)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.16

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.036

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.8

PhyloP100

0.25

PROVEAN

Benign

1.0

REVEL

Benign

0.023

Sift

Benign

0.88

Sift4G

Benign

0.79

Polyphen

0.0

Vest4

0.0030

MutPred

0.36

Gain of glycosylation at C529 (P = 0.0043)

MPC

0.14

ClinPred

0.0026

GERP RS

1.9

Varity_R

0.025

gMVP

0.28

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over