Genetic Variant ERCC4:c.208-807G>C (chr16-13921224-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005236.3(ERCC4):c.208-807G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,008 control chromosomes in the GnomAD database, including 4,404 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4404 hom., cov: 32)

Consequence

ERCC4
NM_005236.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.748

Publications

28 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:

LOC105371093 (HGNC:):

LOC105371093 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ERCC4	NM_005236.3 link	c.208-807G>C	intron_variant	Intron 1 of 10	ENST00000311895.8	NP_005227.1	Q92889-1A0A1W1GSK9
ERCC4	XM_011522424.4 link	c.208-807G>C	intron_variant	Intron 1 of 11		XP_011520726.1	A0A804HKF9
LOC105371093	XR_007064999.1 link	n.82+5301C>G	intron_variant	Intron 1 of 2
LOC105371093	XR_007065000.1 link	n.82+5301C>G	intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8 link	c.208-807G>C		intron_variant	Intron 1 of 10	1	NM_005236.3	ENSP00000310520.7		Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35336

AN:

151890

Hom.:

4400

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.297

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.257

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.261

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.233

AC:

35357

AN:

152008

Hom.:

4404

Cov.:

AF XY:

0.230

AC XY:

17103

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.175

AC:

7266

AN:

41440

American (AMR)

AF:

0.183

AC:

2791

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

984

AN:

3466

East Asian (EAS)

AF:

0.257

AC:

1325

AN:

5154

South Asian (SAS)

AF:

0.246

AC:

1185

AN:

4812

European-Finnish (FIN)

AF:

0.229

AC:

2421

AN:

10572

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.272

AC:

18466

AN:

67978

Other (OTH)

AF:

0.264

AC:

556

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1357

2713

4070

5426

6783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<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:

0.251

Hom.:

600

Bravo

AF:

0.227

Asia WGS

AF:

0.280

AC:

974

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.4

(source)

DANN

Benign

0.67

PhyloP100

0.75

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over