rs1799801

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005236.3(ERCC4):c.2505T>C(p.Ser835Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,896 control chromosomes in the GnomAD database, including 66,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5045 hom., cov: 32)

Exomes 𝑓: 0.29 ( 61143 hom. )

Consequence

ERCC4
NM_005236.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -3.35

Publications

91 publications found

Variant links:

Genes affected

ERCC4 (HGNC:3436): (ERCC excision repair 4, endonuclease catalytic subunit) The protein encoded by this gene forms a complex with ERCC1 and is involved in the 5' incision made during nucleotide excision repair. This complex is a structure specific DNA repair endonuclease that interacts with EME1. Defects in this gene are a cause of xeroderma pigmentosum complementation group F (XP-F), or xeroderma pigmentosum VI (XP6).[provided by RefSeq, Mar 2009]

ERCC4 Gene-Disease associations (from GenCC):

xeroderma pigmentosum group F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
Fanconi anemia complementation group Q
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
XFE progeroid syndrome
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
Fanconi anemia
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

ERCC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-13948101-T-C is Benign according to our data. Variant chr16-13948101-T-C is described in ClinVar as Benign. ClinVar VariationId is 129007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.35 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3 link	c.2505T>C	p.Ser835Ser	synonymous_variant	Exon 11 of 11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 link	c.2643T>C	p.Ser881Ser	synonymous_variant	Exon 12 of 12		XP_011520726.1	A0A804HKF9
ERCC4	XM_047433774.1 link	c.1716T>C	p.Ser572Ser	synonymous_variant	Exon 8 of 8		XP_047289730.1
ERCC4	XM_011522427.2 link	c.1155T>C	p.Ser385Ser	synonymous_variant	Exon 6 of 6		XP_011520729.1	B4DXD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 link	c.2505T>C	p.Ser835Ser	synonymous_variant	Exon 11 of 11	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.250

AC:

37968

AN:

151962

Hom.:

5036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.340

Gnomad AMR

AF:

0.249

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.249

Gnomad SAS

AF:

0.302

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.290

GnomAD2 exomes

AF:

0.272

AC:

68347

AN:

251224

AF XY:

0.279

show subpopulations

Gnomad AFR exome

AF:

0.173

Gnomad AMR exome

AF:

0.233

Gnomad ASJ exome

AF:

0.312

Gnomad EAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.294

Gnomad OTH exome

AF:

0.292

GnomAD4 exome

AF:

0.287

AC:

419607

AN:

1461816

Hom.:

61143

Cov.:

AF XY:

0.290

AC XY:

210714

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.169

AC:

5670

AN:

33480

American (AMR)

AF:

0.239

AC:

10668

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

8191

AN:

26136

East Asian (EAS)

AF:

0.235

AC:

9330

AN:

39698

South Asian (SAS)

AF:

0.318

AC:

27429

AN:

86256

European-Finnish (FIN)

AF:

0.238

AC:

12699

AN:

53418

Middle Eastern (MID)

AF:

0.374

AC:

2158

AN:

5768

European-Non Finnish (NFE)

AF:

0.294

AC:

326454

AN:

1111954

Other (OTH)

AF:

0.282

AC:

17008

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

18928

37856

56785

75713

94641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10810

21620

32430

43240

54050

<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:

0.250

AC:

38007

AN:

152080

Hom.:

5045

Cov.:

AF XY:

0.248

AC XY:

18465

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.174

AC:

7216

AN:

41482

American (AMR)

AF:

0.249

AC:

3810

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1059

AN:

3472

East Asian (EAS)

AF:

0.249

AC:

1288

AN:

5172

South Asian (SAS)

AF:

0.305

AC:

1465

AN:

4810

European-Finnish (FIN)

AF:

0.241

AC:

2550

AN:

10576

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.288

AC:

19592

AN:

67974

Other (OTH)

AF:

0.292

AC:

616

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1425

2850

4274

5699

7124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.281

Hom.:

17391

Bravo

AF:

0.247

Asia WGS

AF:

0.304

AC:

1057

AN:

3478

EpiCase

AF:

0.305

EpiControl

AF:

0.299

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group F

Benign:3

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

XFE progeroid syndrome

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fanconi anemia complementation group Q

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.13

(source)

DANN

Benign

0.45

PhyloP100

-3.3

Mutation Taster

=96/4

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