rs2276465

Positions:

• chr16-13949157-G-A
• chr16-13949157-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005236.3(ERCC4):​c.*810G>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 0.304 in 232,858 control chromosomes in the GnomAD database, including 11,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.29 (6930 hom., cov: 32)
  • Exomes 𝑓: 0.32 (4248 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.46

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 16-13949157-G-A is Benign according to our data. Variant chr16-13949157-G-A is described in ClinVar as [Benign]. Clinvar id is 317837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.*810G>A		3_prime_UTR_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.*810G>A		3_prime_UTR_variant	12/12
ERCC4	XM_011522427.2	c.*810G>A		3_prime_UTR_variant	6/6
ERCC4	XM_047433774.1	c.*810G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.*810G>A		3_prime_UTR_variant	11/11	1	NM_005236.3	P1
ERCC4	ENST00000682617.1	c.*810G>A		3_prime_UTR_variant	12/12
ERCC4	ENST00000683962.1	c.*3255G>A		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44765 AN: 151968 Hom.: 6917 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.321 AC: 25965 AN: 80772 Hom.: 4248 Cov.: 0 AF XY: 0.326 AC XY: 12109 AN XY: 37120

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.384

Gnomad4 EAS exome AF: 0.231

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.345

Gnomad4 OTH exome AF: 0.331

GnomAD4 genome AF: 0.295 AC: 44805 AN: 152086 Hom.: 6930 Cov.: 32 AF XY: 0.292 AC XY: 21728 AN XY: 74354

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.252

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.241

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.328

Alfa AF: 0.277 Hom.: 1899

Bravo AF: 0.289

Asia WGS AF: 0.290 AC: 1011 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0040
DANN	Benign	0.46

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: rs2276465; hg19: chr16-14043014;