NM_005236.3:c.2395C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3PP3PP5BP4

The NM_005236.3(ERCC4):c.2395C>T(p.Arg799Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000629 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000914705: Functional rescue studies showed that the variant could only partially rescue the nuclear excision repair defect and that the variant protein mislocalized to the cytoplasm (Sijbers et al. 1998" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00077 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 0 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20U:5O:2

Conservation

PhyloP100: 5.39

Publications

51 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: ClinGen, G2P, Genomics England PanelApp
Fanconi anemia complementation group Q
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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: Uncertain_significance. The variant received 5 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000914705: Functional rescue studies showed that the variant could only partially rescue the nuclear excision repair defect and that the variant protein mislocalized to the cytoplasm (Sijbers et al. 1998; Ahmad et al. 2010).; SCV002012437: "In vitro functional assays in LCLs (Epstein–Barr virus transformed lymphoblastoid cell lines) and fibroblasts have shown that this variant causes reduced protein expression of nuclear ERCC4 which is attributed to protein mislocalization and can result in decreased cell survival and DNA replication after ultraviolet light exposure (PS3; PMID: 20221251, 29105242, 9579555)."; SCV002587792: Functional studies suggest this variant is functionally defective (PMID: 9579555, 20221251) (PS3).; SCV002522019: Published functional studies demonstrate R799W decreased activity compared to wild-type (Ahmad et al., 2010).; SCV000548332: Experimental studies have shown that this missense change affects ERCC4 function (PMID: 9579555, 20221251).; SCV005402101: in vitro functional assays in LCLs (Epstein–Barr virus transformed lymphoblastoid cell lines) and fibroblasts have shown that this variant causes reduced protein expression of nuclear ERCC4 which is attributed to protein mislocalization and can result in decreased cell survival and DNA replication after ultraviolet light exposure (PMID: 20221251, 29105242, 9579555).; SCV002548369: "At least one publication reports experimental evidence evaluating an impact on protein function (Sijbers_1998, Ahmad_2010)."

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, MutationAssessor, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 16-13947991-C-T is Pathogenic according to our data. Variant chr16-13947991-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16580.

BP4

Computational evidence support a benign effect (MetaRNN=0.09623465). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.2395C>T	p.Arg799Trp	missense	Exon 11 of 11	NP_005227.1	Q92889-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.2395C>T	p.Arg799Trp	missense	Exon 11 of 11	ENSP00000310520.7	Q92889-1
ERCC4	ENST00000682617.1		c.2533C>T	p.Arg845Trp	missense	Exon 12 of 12	ENSP00000507912.1	A0A804HKF9
ERCC4	ENST00000389138.7	TSL:2	n.1672C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000481

AC:

121

AN:

251312

AF XY:

0.000442

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000889

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000614

AC:

898

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

467

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000748

AC:

832

AN:

1112008

Other (OTH)

AF:

0.000248

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000768

AC:

117

AN:

152286

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41574

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.000737

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Xeroderma pigmentosum, group F (8)

not provided (4)

Fanconi anemia complementation group Q (2)

Xeroderma pigmentosum (2)

Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q (2)

Breast carcinoma (1)

Carcinoma of pancreas (1)

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (2)

ERCC4-related disorder (1)

Hutchinson-Gilford syndrome (1)

not specified (2)

XFE progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.0019

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.096

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.7

PhyloP100

5.4

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MVP

0.71

MPC

0.45

ClinPred

0.31

GERP RS

6.2

Varity_R

0.93

gMVP

0.83

Mutation Taster

=17/83

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over