rs4781563

Positions:

• chr16-13951542-G-A

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.*3195G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 211,784 control chromosomes in the GnomAD database, including 6,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4512 hom., cov: 32)
  • Exomes 𝑓: 0.27 (2158 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.504

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-13951542-G-A is Benign according to our data. Variant chr16-13951542-G-A is described in ClinVar as [Benign]. Clinvar id is 317868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.*3195G>A		3_prime_UTR_variant	11/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.*3195G>A		3_prime_UTR_variant	12/12		XP_011520726.1
ERCC4	XM_047433774.1	c.*3195G>A		3_prime_UTR_variant	8/8		XP_047289730.1
ERCC4	XM_011522427.2	c.*3195G>A		3_prime_UTR_variant	6/6		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.*3195G>A		3_prime_UTR_variant	11/11	1	NM_005236.3	ENSP00000310520.7
ERCC4	ENST00000682617.1	c.*3195G>A		3_prime_UTR_variant	12/12			ENSP00000507912.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35602 AN: 151894 Hom.: 4508 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.265 AC: 15857 AN: 59770 Hom.: 2158 Cov.: 0 AF XY: 0.270 AC XY: 7515 AN XY: 27816

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.211

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.275

GnomAD4 genome AF: 0.234 AC: 35626 AN: 152014 Hom.: 4512 Cov.: 32 AF XY: 0.232 AC XY: 17223 AN XY: 74308

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.271

Alfa AF: 0.280 Hom.: 6669

Bravo AF: 0.228

Asia WGS AF: 0.268 AC: 934 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group F Benign:1

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:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.66

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: rs4781563; hg19: chr16-14045399;