rs4781563

Variant names:

Variant summary

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

The NM_005236.3(ERCC4):c.*3195G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 211,784 control chromosomes in the GnomAD database, including 6,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4512 hom., cov: 32)

Exomes 𝑓: 0.27 ( 2158 hom. )

Consequence

ERCC4
NM_005236.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.504

Publications

21 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-13951542-G-A is Benign according to our data. Variant chr16-13951542-G-A is described in ClinVar as Benign. ClinVar VariationId is 317868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3 link	c.*3195G>A	3_prime_UTR_variant	Exon 11 of 11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 link	c.*3195G>A	3_prime_UTR_variant	Exon 12 of 12		XP_011520726.1	A0A804HKF9
ERCC4	XM_047433774.1 link	c.*3195G>A	3_prime_UTR_variant	Exon 8 of 8		XP_047289730.1
ERCC4	XM_011522427.2 link	c.*3195G>A	3_prime_UTR_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.*3195G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_005236.3	ENSP00000310520.7		Q92889-1
ERCC4	ENST00000682617.1 link	c.*3195G>A		3_prime_UTR_variant	Exon 12 of 12			ENSP00000507912.1		A0A804HKF9

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35602

AN:

151894

Hom.:

4508

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.301

Gnomad AMR

AF:

0.187

Gnomad ASJ

AF:

0.295

Gnomad EAS

AF:

0.235

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.269

GnomAD4 exome

AF:

0.265

AC:

15857

AN:

59770

Hom.:

2158

Cov.:

AF XY:

0.270

AC XY:

7515

AN XY:

27816

show subpopulations

African (AFR)

AF:

0.155

AC:

420

AN:

2704

American (AMR)

AF:

0.183

AC:

327

AN:

1784

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1154

AN:

3854

East Asian (EAS)

AF:

0.211

AC:

1861

AN:

8840

South Asian (SAS)

AF:

0.237

AC:

122

AN:

514

European-Finnish (FIN)

AF:

0.238

AC:

AN:

Middle Eastern (MID)

AF:

0.311

AC:

115

AN:

370

European-Non Finnish (NFE)

AF:

0.286

AC:

10465

AN:

36642

Other (OTH)

AF:

0.275

AC:

1383

AN:

5020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

590

1181

1771

2362

2952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.234

AC:

35626

AN:

152014

Hom.:

4512

Cov.:

AF XY:

0.232

AC XY:

17223

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.165

AC:

6838

AN:

41454

American (AMR)

AF:

0.187

AC:

2856

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.295

AC:

1025

AN:

3470

East Asian (EAS)

AF:

0.235

AC:

1216

AN:

5170

South Asian (SAS)

AF:

0.244

AC:

1174

AN:

4818

European-Finnish (FIN)

AF:

0.235

AC:

2484

AN:

10556

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19092

AN:

67950

Other (OTH)

AF:

0.271

AC:

573

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1406

2812

4218

5624

7030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.269

Hom.:

17714

Bravo

AF:

0.228

Asia WGS

AF:

0.268

AC:

934

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group F

Benign:1

Jan 12, 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.36

(source)

DANN

Benign

0.66

PhyloP100

-0.50

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