16-13948831-G-T

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.*484G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 232,326 control chromosomes in the GnomAD database, including 15,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (10412 hom., cov: 31)
  • Exomes 𝑓: 0.34 (4699 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84

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=-1.01).
• BP6: Variant 16-13948831-G-T is Benign according to our data. Variant chr16-13948831-G-T is described in ClinVar as [Benign]. Clinvar id is 317830.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.*484G>T		3_prime_UTR_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.*484G>T		3_prime_UTR_variant	12/12
ERCC4	XM_011522427.2	c.*484G>T		3_prime_UTR_variant	6/6
ERCC4	XM_047433774.1	c.*484G>T		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.*484G>T		3_prime_UTR_variant	11/11	1	NM_005236.3	P1
ERCC4	ENST00000682617.1	c.*484G>T		3_prime_UTR_variant	12/12
ERCC4	ENST00000683962.1	c.*2929G>T		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55305 AN: 151730 Hom.: 10381 Cov.: 31

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.379

GnomAD4 exome AF: 0.339 AC: 27278 AN: 80478 Hom.: 4699 Cov.: 0 AF XY: 0.341 AC XY: 12633 AN XY: 37022

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.385

Gnomad4 EAS exome AF: 0.230

Gnomad4 SAS exome AF: 0.308

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.348

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.365 AC: 55401 AN: 151848 Hom.: 10412 Cov.: 31 AF XY: 0.362 AC XY: 26853 AN XY: 74186

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.314

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.343

Gnomad4 OTH AF: 0.380

Alfa AF: 0.359 Hom.: 2192

Bravo AF: 0.371

Asia WGS AF: 0.326 AC: 1135 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.16
Dann	Benign	0.63

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: rs3743538; hg19: chr16-14042688; COSMIC: COSV61313346; COSMIC: COSV61313346;