rs1800067

chr16-13935176-G-Achr16-13935176-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005236.3(ERCC4):c.1244G>A(p.Arg415Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,408 control chromosomes in the GnomAD database, including 4,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R415G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (326 hom., cov: 32)
  • Exomes 𝑓: 0.069 (4131 hom.)
• Consequence: ERCC4 NM_005236.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 9.60

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030626655).
• BP6: Variant 16-13935176-G-A is Benign according to our data. Variant chr16-13935176-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13935176-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.1244G>A	p.Arg415Gln	missense_variant	8/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.1382G>A	p.Arg461Gln	missense_variant	9/12
ERCC4	XM_047433774.1	c.455G>A	p.Arg152Gln	missense_variant	5/8
ERCC4	XM_011522427.2	c.-107G>A		5_prime_UTR_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.1244G>A	p.Arg415Gln	missense_variant	8/11	1	NM_005236.3	P1
	ENST00000570663.1	n.219+241C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8111 AN: 152174 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0376

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0823

GnomAD3 exomes AF: 0.0561 AC: 14090 AN: 251016 Hom.: 568 AF XY: 0.0586 AC XY: 7958 AN XY: 135700

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0452

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.0354

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0733

GnomAD4 exome AF: 0.0695 AC: 101541 AN: 1461116 Hom.: 4131 Cov.: 32 AF XY: 0.0695 AC XY: 50529 AN XY: 726926

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.0484

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.0382

Gnomad4 NFE exome AF: 0.0770

Gnomad4 OTH exome AF: 0.0664

GnomAD4 genome AF: 0.0532 AC: 8108 AN: 152292 Hom.: 326 Cov.: 32 AF XY: 0.0518 AC XY: 3856 AN XY: 74466

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0660

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0356

Gnomad4 FIN AF: 0.0376

Gnomad4 NFE AF: 0.0772

Gnomad4 OTH AF: 0.0810

Alfa AF: 0.0764 Hom.: 1246

Bravo AF: 0.0539

TwinsUK AF: 0.0763 AC: 283

ALSPAC AF: 0.0810 AC: 312

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.0765 AC: 658

ExAC AF: 0.0556 AC: 6747

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0881

EpiControl AF: 0.0863

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 13, 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. -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2019

This variant is associated with the following publications: (PMID: 24802942, 27153395, 24651674) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.27
MPC		0.46
ClinPred		0.037	T
GERP RS		5.8
Varity_R		0.67
gMVP		0.59

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

Other links and lift over

dbSNP: rs1800067; hg19: chr16-14029033; COSMIC: COSV61311508; COSMIC: COSV61311508;