16-13948831-G-T

Variant names:

• chr16-13948831-G-T
• rs3743538
• NM_005236.3:c.*484G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.84
• Publications: 12 publications found

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]

ERCC4 Gene-Disease associations (from GenCC):

• xeroderma pigmentosum group F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• XFE progeroid syndrome

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• xeroderma pigmentosum-Cockayne syndrome complex

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 317830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.*484G>T		3_prime_UTR	Exon 11 of 11	NP_005227.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.*484G>T		3_prime_UTR	Exon 11 of 11	ENSP00000310520.7
	ERCC4	ENST00000683962.1		n.*2929G>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000506854.1
	ERCC4	ENST00000682617.1		c.*484G>T		3_prime_UTR	Exon 12 of 12	ENSP00000507912.1

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

African (AFR) AF: 0.433 AC: 1673 AN: 3864

American (AMR) AF: 0.355 AC: 878 AN: 2474

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1957 AN: 5080

East Asian (EAS) AF: 0.230 AC: 2609 AN: 11320

South Asian (SAS) AF: 0.308 AC: 221 AN: 718

European-Finnish (FIN) AF: 0.333 AC: 20 AN: 60

Middle Eastern (MID) AF: 0.403 AC: 196 AN: 486

European-Non Finnish (NFE) AF: 0.348 AC: 17305 AN: 49770

Other (OTH) AF: 0.361 AC: 2419 AN: 6706

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

African (AFR) AF: 0.442 AC: 18309 AN: 41430

American (AMR) AF: 0.338 AC: 5171 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1313 AN: 3460

East Asian (EAS) AF: 0.242 AC: 1235 AN: 5098

South Asian (SAS) AF: 0.314 AC: 1510 AN: 4804

European-Finnish (FIN) AF: 0.309 AC: 3255 AN: 10540

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23283 AN: 67912

Other (OTH) AF: 0.380 AC: 804 AN: 2114

Alfa AF: 0.358 Hom.: 3887

Bravo AF: 0.371

Asia WGS AF: 0.326 AC: 1135 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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.63
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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