rs2276465

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.*810G>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 0.304 in 232,858 control chromosomes in the GnomAD database, including 11,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 6930 hom., cov: 32)

Exomes 𝑓: 0.32 ( 4248 hom. )

Consequence

ERCC4
NM_005236.3 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.46

Publications

15 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=-1.0).

BP6

Variant 16-13949157-G-A is Benign according to our data. Variant chr16-13949157-G-A is described in ClinVar as Benign. ClinVar VariationId is 317837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3 link	c.*810G>A	3_prime_UTR_variant	Exon 11 of 11	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 link	c.*810G>A	3_prime_UTR_variant	Exon 12 of 12		XP_011520726.1	A0A804HKF9
ERCC4	XM_047433774.1 link	c.*810G>A	3_prime_UTR_variant	Exon 8 of 8		XP_047289730.1
ERCC4	XM_011522427.2 link	c.*810G>A	3_prime_UTR_variant	Exon 6 of 6		XP_011520729.1	B4DXD8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERCC4	ENST00000311895.8 link	c.*810G>A	3_prime_UTR_variant	Exon 11 of 11	1	NM_005236.3	ENSP00000310520.7	Q92889-1
ERCC4	ENST00000683962.1 link	n.*3255G>A	non_coding_transcript_exon_variant	Exon 12 of 12			ENSP00000506854.1	A0A804HI16
ERCC4	ENST00000682617.1 link	c.*810G>A	3_prime_UTR_variant	Exon 12 of 12			ENSP00000507912.1	A0A804HKF9
ERCC4	ENST00000683962.1 link	n.*3255G>A	3_prime_UTR_variant	Exon 12 of 12			ENSP00000506854.1	A0A804HI16

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44765

AN:

151968

Hom.:

6917

Cov.:

show subpopulations

Gnomad AFR

AF:

0.230

Gnomad AMI

AF:

0.424

Gnomad AMR

AF:

0.253

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.241

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.326

GnomAD4 exome

AF:

0.321

AC:

25965

AN:

80772

Hom.:

4248

Cov.:

AF XY:

0.326

AC XY:

12109

AN XY:

37120

show subpopulations

African (AFR)

AF:

0.227

AC:

883

AN:

3888

American (AMR)

AF:

0.252

AC:

630

AN:

2496

Ashkenazi Jewish (ASJ)

AF:

0.384

AC:

1960

AN:

5104

East Asian (EAS)

AF:

0.231

AC:

2629

AN:

11370

South Asian (SAS)

AF:

0.259

AC:

181

AN:

700

European-Finnish (FIN)

AF:

0.350

AC:

AN:

Middle Eastern (MID)

AF:

0.386

AC:

190

AN:

492

European-Non Finnish (NFE)

AF:

0.345

AC:

17238

AN:

49906

Other (OTH)

AF:

0.331

AC:

2233

AN:

6756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

872

1744

2615

3487

4359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.295

AC:

44805

AN:

152086

Hom.:

6930

Cov.:

AF XY:

0.292

AC XY:

21728

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.231

AC:

9571

AN:

41466

American (AMR)

AF:

0.252

AC:

3845

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1314

AN:

3468

East Asian (EAS)

AF:

0.241

AC:

1249

AN:

5178

South Asian (SAS)

AF:

0.265

AC:

1281

AN:

4828

European-Finnish (FIN)

AF:

0.309

AC:

3265

AN:

10576

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.340

AC:

23084

AN:

67990

Other (OTH)

AF:

0.328

AC:

692

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1631

3262

4894

6525

8156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.286

Hom.:

2530

Bravo

AF:

0.289

Asia WGS

AF:

0.290

AC:

1011

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 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. -

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

-1.0

CADD

Benign

0.0040

(source)

DANN

Benign

0.46

PhyloP100

-4.5

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