rs201181735

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005236.3(ERCC4):c.974-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,666 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 6 hom. )

Consequence

ERCC4
NM_005236.3 splice_region, intron

Scores

Splicing: ADA: 0.0003965

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.0500

Publications

1 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:

ENSG00000262732 (HGNC:):

ENSG00000262732 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 16-13932151-T-C is Benign according to our data. Variant chr16-13932151-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218668.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00106 (161/152328) while in subpopulation SAS AF = 0.00435 (21/4828). AF 95% confidence interval is 0.00291. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ERCC4	NM_005236.3 link	c.974-6T>C	splice_region_variant, intron_variant	Intron 5 of 10	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4 link	c.1112-6T>C	splice_region_variant, intron_variant	Intron 6 of 11		XP_011520726.1
ERCC4	XM_047433774.1 link	c.185-6T>C	splice_region_variant, intron_variant	Intron 2 of 7		XP_047289730.1
ERCC4	XM_011522427.2 link	c.-502T>C	upstream_gene_variant			XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 link	c.974-6T>C		splice_region_variant, intron_variant	Intron 5 of 10	1	NM_005236.3	ENSP00000310520.7

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

162

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00133

AC:

334

AN:

251244

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00172

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00122

AC:

1788

AN:

1460338

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

964

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33452

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00335

AC:

289

AN:

86228

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00368

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00123

AC:

1364

AN:

1110770

Other (OTH)

AF:

0.00121

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00106

AC:

161

AN:

152328

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41578

American (AMR)

AF:

0.000392

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00435

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00172

AC:

117

AN:

68034

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

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:

0.00130

Hom.:

Bravo

AF:

0.000982

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 13, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 31, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ERCC4: BP4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary cancer-predisposing syndrome

Uncertain:1

Sep 17, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4 ERCC4:c.974-6T>C is an intronic variant located close to a canonical splice site. This variant is found in 335/268132 alleles at a frequency of 0.124% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been reported in the ClinVar database (1x benign, 6x likely benign) and in LOVD (1x likely benign). Based on currently available information, the variant c.974-6T>C should be considered an uncertain significance variant.

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

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Xeroderma pigmentosum

Benign:1

Jan 31, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Xeroderma pigmentosum, group F

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.1

(source)

DANN

Benign

0.74

PhyloP100

0.050

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00040

dbscSNV1_RF

Benign

0.018

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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