rs2020955

Positions:

chr16-13944802-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005236.3(ERCC4):c.1984T>C(p.Ser662Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,613,574 control chromosomes in the GnomAD database, including 1,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 904 hom., cov: 32)

Exomes 𝑓: 0.0067 ( 815 hom. )

Consequence

ERCC4
NM_005236.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.463

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011295676).

BP6

Variant 16-13944802-T-C is Benign according to our data. Variant chr16-13944802-T-C is described in ClinVar as [Benign]. Clinvar id is 134134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ERCC4	NM_005236.3 linkuse as main transcript	c.1984T>C	p.Ser662Pro	missense_variant	10/11	ENST00000311895.8
ERCC4	XM_011522424.4 linkuse as main transcript	c.2122T>C	p.Ser708Pro	missense_variant	11/12
ERCC4	XM_047433774.1 linkuse as main transcript	c.1195T>C	p.Ser399Pro	missense_variant	7/8
ERCC4	XM_011522427.2 linkuse as main transcript	c.634T>C	p.Ser212Pro	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8 linkuse as main transcript	c.1984T>C	p.Ser662Pro	missense_variant	10/11	1	NM_005236.3	P1	Q92889-1

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8952

AN:

152194

Hom.:

903

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0239

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.0473

GnomAD3 exomes

AF:

0.0157

AC:

3954

AN:

251158

Hom.:

329

AF XY:

0.0120

AC XY:

1631

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00784

GnomAD4 exome

AF:

0.00669

AC:

9778

AN:

1461262

Hom.:

815

Cov.:

AF XY:

0.00588

AC XY:

4273

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.000701

Gnomad4 OTH exome

AF:

0.0137

GnomAD4 genome

AF:

0.0589

AC:

8967

AN:

152312

Hom.:

904

Cov.:

AF XY:

0.0561

AC XY:

4178

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.202

Gnomad4 AMR

AF:

0.0238

Gnomad4 ASJ

AF:

0.0104

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.0468

Alfa

AF:

0.0130

Hom.:

265

Bravo

AF:

0.0669

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.192

AC:

845

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.0190

AC:

2304

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Xeroderma pigmentosum, group F

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2019	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.5

DANN

Benign

0.66

DEOGEN2

Benign

0.085

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.27

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.31

REVEL

Benign

0.015

Sift

Benign

0.43

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.099

MPC

0.098

ClinPred

0.000022

GERP RS

0.88

Varity_R

0.074

gMVP

0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over