NM_000123.4:c.2877A>C

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.2877A>C(p.Arg959Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000627 in 1,614,174 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

ERCC5
NM_000123.4 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2O:1

Conservation

PhyloP100: 3.91

Publications

3 publications found

Variant links:

COSMIC-nc: COSV63245437

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=0.010380447).

BP6

Variant 13-102872396-A-C is Benign according to our data. Variant chr13-102872396-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00341 (519/152308) while in subpopulation AFR AF = 0.0118 (492/41578). AF 95% confidence interval is 0.011. There are 3 homozygotes in GnomAd4. There are 237 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.2877A>C	p.Arg959Ser	missense_variant, splice_region_variant	Exon 13 of 15	ENST00000652225.2	NP_000114.3	P28715-1
BIVM-ERCC5	NM_001204425.2 link	c.4239A>C	p.Arg1413Ser	missense_variant, splice_region_variant	Exon 21 of 23		NP_001191354.2	R4GMW8Q59FZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERCC5	ENST00000652225.2 link	c.2877A>C	p.Arg959Ser	missense_variant, splice_region_variant	Exon 13 of 15		NM_000123.4	ENSP00000498881.2	P28715-1
BIVM-ERCC5	ENST00000639435.1 link	c.4239A>C	p.Arg1413Ser	missense_variant, splice_region_variant	Exon 23 of 25	5		ENSP00000491742.1	R4GMW8
BIVM-ERCC5	ENST00000639132.1 link	c.3552A>C	p.Arg1184Ser	missense_variant, splice_region_variant	Exon 22 of 24	5		ENSP00000492684.1	A0A1W2PS85

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

521

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00103

AC:

258

AN:

251364

AF XY:

0.000846

show subpopulations

Gnomad AFR exome

AF:

0.0134

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000337

AC:

493

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

222

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0108

AC:

361

AN:

33480

American (AMR)

AF:

0.000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1112002

Other (OTH)

AF:

0.000894

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00341

AC:

519

AN:

152308

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

237

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0118

AC:

492

AN:

41578

American (AMR)

AF:

0.00118

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00134

Hom.:

Bravo

AF:

0.00414

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00123

AC:

150

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Nov 24, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ERCC5 p.Arg959Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs41281674) and ClinVar (classification not provided, submitted by ITMI). The variant was identified in control databases in 360 of 282766 chromosomes (1 homozygous) at a frequency of 0.001273 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 317 of 24960 chromosomes (freq: 0.0127), Other in 7 of 7222 chromosomes (freq: 0.000969), Latino in 30 of 35422 chromosomes (freq: 0.000847), European (Finnish) in 1 of 25122 chromosomes (freq: 0.00004) and European (non-Finnish) in 5 of 129120 chromosomes (freq: 0.000039), but was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Arg959 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Arg959Ser variant occurs in the third last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is 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

Pathogenic

0.84

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

.;.;.;D;.

Eigen

Benign

0.012

Eigen_PC

Benign

0.081

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

T;T;.;T;T

MetaRNN

Benign

0.010

T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.6

.;.;.;M;.

PhyloP100

3.9

PROVEAN

Pathogenic

-4.5

.;.;.;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.012

.;.;.;D;D

Sift4G

Uncertain

0.0050

.;.;.;D;D

Polyphen

0.26

.;.;.;B;.

Vest4

0.76, 0.79

MutPred

0.59

.;.;.;Gain of catalytic residue at R964 (P = 0.001);.;

MVP

0.90

MPC

0.15

ClinPred

0.087

GERP RS

3.1

Varity_R

0.77

gMVP

0.68

Mutation Taster

=83/17

polymorphism

(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