16-13949318-C-G

Variant names:

• chr16-13949318-C-G
• rs2276466
• NM_005236.3:c.*971C>G

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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.14
• Publications: 43 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=-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 VariationId is 317841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
ERCC4	NM_005236.3	c.*971C>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000311895.8	NP_005227.1
ERCC4	XM_011522424.4	c.*971C>G		3_prime_UTR_variant	Exon 12 of 12		XP_011520726.1
ERCC4	XM_047433774.1	c.*971C>G		3_prime_UTR_variant	Exon 8 of 8		XP_047289730.1
ERCC4	XM_011522427.2	c.*971C>G		3_prime_UTR_variant	Exon 6 of 6		XP_011520729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC4	ENST00000311895.8	c.*971C>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_005236.3	ENSP00000310520.7
ERCC4	ENST00000683962.1	n.*3416C>G		non_coding_transcript_exon_variant	Exon 12 of 12			ENSP00000506854.1
ERCC4	ENST00000682617.1	c.*971C>G		3_prime_UTR_variant	Exon 12 of 12			ENSP00000507912.1
ERCC4	ENST00000683962.1	n.*3416C>G		3_prime_UTR_variant	Exon 12 of 12			ENSP00000506854.1

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

African (AFR) AF: 0.163 AC: 637 AN: 3898

American (AMR) AF: 0.267 AC: 669 AN: 2506

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1608 AN: 5138

East Asian (EAS) AF: 0.230 AC: 2651 AN: 11506

South Asian (SAS) AF: 0.308 AC: 218 AN: 708

European-Finnish (FIN) AF: 0.185 AC: 37 AN: 200

Middle Eastern (MID) AF: 0.352 AC: 174 AN: 494

European-Non Finnish (NFE) AF: 0.292 AC: 14696 AN: 50314

Other (OTH) AF: 0.283 AC: 1924 AN: 6788

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

African (AFR) AF: 0.168 AC: 6968 AN: 41474

American (AMR) AF: 0.248 AC: 3789 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1054 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1242 AN: 5178

South Asian (SAS) AF: 0.302 AC: 1456 AN: 4816

European-Finnish (FIN) AF: 0.241 AC: 2546 AN: 10552

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.286 AC: 19475 AN: 67992

Other (OTH) AF: 0.287 AC: 605 AN: 2106

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Xeroderma pigmentosum, group F Benign:1

Jan 13, 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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.73
DANN	Benign	0.51
PhyloP100		-2.1
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: rs2276466; hg19: chr16-14043175;