rs56012340

Positions:

• chr16-13950924-C-A
• chr16-13950924-C-T

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.*2577C>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 0.24 in 195,684 control chromosomes in the GnomAD database, including 5,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4462 hom., cov: 32)
  • Exomes 𝑓: 0.26 (1525 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.351

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=-0.92).
• BP6: Variant 16-13950924-C-A is Benign according to our data. Variant chr16-13950924-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 210952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.*2577C>A		3_prime_UTR_variant	11/11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.*2577C>A		3_prime_UTR_variant	12/12		XP_011520726.1
ERCC4	XM_011522427.2	c.*2577C>A		3_prime_UTR_variant	6/6		XP_011520729.1
ERCC4	XM_047433774.1	c.*2577C>A		3_prime_UTR_variant	8/8		XP_047289730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.*2577C>A		3_prime_UTR_variant	11/11	1	NM_005236.3	ENSP00000310520	P1
ERCC4	ENST00000682617.1	c.*2577C>A		3_prime_UTR_variant	12/12			ENSP00000507912

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35470 AN: 151522 Hom.: 4458 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.270

GnomAD4 exome AF: 0.259 AC: 11416 AN: 44046 Hom.: 1525 Cov.: 0 AF XY: 0.266 AC XY: 5438 AN XY: 20476

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.234 AC: 35493 AN: 151638 Hom.: 4462 Cov.: 32 AF XY: 0.231 AC XY: 17135 AN XY: 74074

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.273

Alfa AF: 0.246 Hom.: 572

Bravo AF: 0.228

Asia WGS AF: 0.268 AC: 934 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 11, 2015

- -

Xeroderma pigmentosum, group F Benign:1

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. -

not provided Benign:1

Likely 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	-0.92
CADD	Benign	0.64
DANN	Benign	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: rs56012340; hg19: chr16-14044781; COSMIC: COSV61313340; COSMIC: COSV61313340;