rs16963255

chr16-13948251-G-Achr16-13948251-G-Cchr16-13948251-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005236.3(ERCC4):c.2655G>A(p.Thr885=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,108 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.013 (181 hom.)
• Consequence: ERCC4 NM_005236.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.79

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-13948251-G-A is Benign according to our data. Variant chr16-13948251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-13948251-G-A is described in Lovd as [Benign]. Variant chr16-13948251-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERCC4	NM_005236.3	c.2655G>A	p.Thr885=	synonymous_variant	11/11	ENST00000311895.8
ERCC4	XM_011522424.4	c.2793G>A	p.Thr931=	synonymous_variant	12/12
ERCC4	XM_047433774.1	c.1866G>A	p.Thr622=	synonymous_variant	8/8
ERCC4	XM_011522427.2	c.1305G>A	p.Thr435=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERCC4	ENST00000311895.8	c.2655G>A	p.Thr885=	synonymous_variant	11/11	1	NM_005236.3	P1
ERCC4	ENST00000682617.1	c.2793G>A	p.Thr931=	synonymous_variant	12/12
ERCC4	ENST00000389138.7	n.1932G>A		non_coding_transcript_exon_variant	6/6	2
ERCC4	ENST00000683962.1	c.*2349G>A		3_prime_UTR_variant, NMD_transcript_variant	12/12

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1515 AN: 152124 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.0107 AC: 2681 AN: 251370 Hom.: 30 AF XY: 0.0108 AC XY: 1471 AN XY: 135852

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00578

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.0129 AC: 18928 AN: 1461866 Hom.: 181 Cov.: 33 AF XY: 0.0130 AC XY: 9423 AN XY: 727234

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00677

Gnomad4 FIN exome AF: 0.0325

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.00965

GnomAD4 genome AF: 0.00996 AC: 1516 AN: 152242 Hom.: 12 Cov.: 32 AF XY: 0.00961 AC XY: 715 AN XY: 74426

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.0111 Hom.: 18

Bravo AF: 0.00747

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Xeroderma pigmentosum, group F Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ERCC4: BP4, BP7, BS1, BS2 -

Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.056
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16963255; hg19: chr16-14042108; COSMIC: COSV104606283; COSMIC: COSV104606283;