16-13948320-C-T

Variant names:

• chr16-13948320-C-T
• rs3136225
• NM_005236.3:c.2724C>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.2724C>T​(p.Val908Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,612,764 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V908V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: ERCC4 NM_005236.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.04
• Publications: 3 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=-0.74).
• BP6: Variant 16-13948320-C-T is Benign according to our data. Variant chr16-13948320-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00271 (413/152192) while in subpopulation NFE AF = 0.00432 (294/68014). AF 95% confidence interval is 0.00392. There are 0 homozygotes in GnomAd4. There are 189 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.2724C>T	p.Val908Val	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.2724C>T	p.Val908Val	synonymous	Exon 11 of 11	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000682617.1		c.2862C>T	p.Val954Val	synonymous	Exon 12 of 12	ENSP00000507912.1	A0A804HKF9
	ERCC4	ENST00000389138.7	TSL:2	n.2001C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 413 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00350 AC: 872 AN: 249160 AF XY: 0.00342

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00420

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00378 AC: 5524 AN: 1460572 Hom.: 17 Cov.: 33 AF XY: 0.00370 AC XY: 2687 AN XY: 726638

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 159 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86234

European-Finnish (FIN) AF: 0.00548 AC: 286 AN: 52166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00434 AC: 4830 AN: 1111974

Other (OTH) AF: 0.00316 AC: 191 AN: 60390

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74400

African (AFR) AF: 0.00144 AC: 60 AN: 41538

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00432 AC: 294 AN: 68014

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00362 Hom.: 0

Bravo AF: 0.00247

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q (1)
-	-	1	Xeroderma pigmentosum (1)
-	-	1	Xeroderma pigmentosum, group F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.047
DANN	Benign	0.58
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs3136225; hg19: chr16-14042177; COSMIC: COSV104606310;