16-13949318-C-G

Position:

• chr16-13949318-C-G

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.*971C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 233,622 control chromosomes in the GnomAD database, including 8,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4938 hom., cov: 32)
  • Exomes 𝑓: 0.28 (3179 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.14

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=-0.82).
• BP6: Variant 16-13949318-C-G is Benign according to our data. Variant chr16-13949318-C-G is described in ClinVar as [Benign]. Clinvar id is 317841.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.*971C>G		3_prime_UTR_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.*971C>G		3_prime_UTR_variant	12/12
ERCC4	XM_011522427.2	c.*971C>G		3_prime_UTR_variant	6/6
ERCC4	XM_047433774.1	c.*971C>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.*971C>G		3_prime_UTR_variant	11/11	1	NM_005236.3	P1
ERCC4	ENST00000682617.1	c.*971C>G		3_prime_UTR_variant	12/12
ERCC4	ENST00000683962.1	c.*3416C>G		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37501 AN: 151952 Hom.: 4929 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.247

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.277 AC: 22614 AN: 81552 Hom.: 3179 Cov.: 0 AF XY: 0.281 AC XY: 10556 AN XY: 37528

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.185

Gnomad4 NFE exome AF: 0.292

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.247 AC: 37539 AN: 152070 Hom.: 4938 Cov.: 32 AF XY: 0.246 AC XY: 18254 AN XY: 74336

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.304

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.302

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.287

Alfa AF: 0.153 Hom.: 336

Bravo AF: 0.244

Asia WGS AF: 0.295 AC: 1028 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	-0.82
CADD	Benign	0.73
DANN	Benign	0.51

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: rs2276466; hg19: chr16-14043175;