rs16963255

Variant names:

• chr16-13948251-G-A
• rs16963255
• NM_005236.3:c.2655G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-13948251-G-A
• chr16-13948251-G-C
• chr16-13948251-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005236.3(ERCC4):​c.2655G>A​(p.Thr885Thr) 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:11
• Conservation: PhyloP100: -3.79
• Publications: 11 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: ClinGen, G2P, Genomics England PanelApp
• Fanconi anemia complementation group Q

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 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 Benign/Likely_benign. ClinVar VariationId is 259684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00996 (1516/152242) while in subpopulation NFE AF = 0.0141 (956/68020). AF 95% confidence interval is 0.0133. There are 12 homozygotes in GnomAd4. There are 715 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.2655G>A	p.Thr885Thr	synonymous	Exon 11 of 11	NP_005227.1	Q92889-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	ENST00000311895.8	TSL:1 MANE Select	c.2655G>A	p.Thr885Thr	synonymous	Exon 11 of 11	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000682617.1		c.2793G>A	p.Thr931Thr	synonymous	Exon 12 of 12	ENSP00000507912.1	A0A804HKF9
	ERCC4	ENST00000389138.7	TSL:2	n.1932G>A		non_coding_transcript_exon	Exon 6 of 6

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

GnomAD2 exomes AF: 0.0107 AC: 2681 AN: 251370 AF XY: 0.0108

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 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

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00677 AC: 584 AN: 86258

European-Finnish (FIN) AF: 0.0325 AC: 1734 AN: 53406

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.0142 AC: 15757 AN: 1112000

Other (OTH) AF: 0.00965 AC: 583 AN: 60396

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

African (AFR) AF: 0.00250 AC: 104 AN: 41556

American (AMR) AF: 0.00425 AC: 65 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3464

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4826

European-Finnish (FIN) AF: 0.0323 AC: 342 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 956 AN: 68020

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.0120 Hom.: 28

Bravo AF: 0.00747

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0110

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Xeroderma pigmentosum, group F (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)
-	-	1	Xeroderma pigmentosum, group F;C1970416:XFE progeroid syndrome;C3808988:Fanconi anemia complementation group Q (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.056
DANN	Benign	0.85
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs16963255; hg19: chr16-14042108; COSMIC: COSV104606283;