rs4781563

Variant names:

• chr16-13951542-G-A
• rs4781563
• NM_005236.3:c.*3195G>A

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.*3195G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 211,784 control chromosomes in the GnomAD database, including 6,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4512 hom., cov: 32)
  • Exomes 𝑓: 0.27 (2158 hom.)
• Consequence: ERCC4 NM_005236.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.504
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-13951542-G-A is Benign according to our data. Variant chr16-13951542-G-A is described in ClinVar as Benign. ClinVar VariationId is 317868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERCC4	NM_005236.3	MANE Select	c.*3195G>A		3_prime_UTR	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.*3195G>A		3_prime_UTR	Exon 11 of 11	ENSP00000310520.7	Q92889-1
	ERCC4	ENST00000682617.1		c.*3195G>A		3_prime_UTR	Exon 12 of 12	ENSP00000507912.1	A0A804HKF9

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35602 AN: 151894 Hom.: 4508 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.265 AC: 15857 AN: 59770 Hom.: 2158 Cov.: 0 AF XY: 0.270 AC XY: 7515 AN XY: 27816

African (AFR) AF: 0.155 AC: 420 AN: 2704

American (AMR) AF: 0.183 AC: 327 AN: 1784

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1154 AN: 3854

East Asian (EAS) AF: 0.211 AC: 1861 AN: 8840

South Asian (SAS) AF: 0.237 AC: 122 AN: 514

European-Finnish (FIN) AF: 0.238 AC: 10 AN: 42

Middle Eastern (MID) AF: 0.311 AC: 115 AN: 370

European-Non Finnish (NFE) AF: 0.286 AC: 10465 AN: 36642

Other (OTH) AF: 0.275 AC: 1383 AN: 5020

GnomAD4 genome AF: 0.234 AC: 35626 AN: 152014 Hom.: 4512 Cov.: 32 AF XY: 0.232 AC XY: 17223 AN XY: 74308

African (AFR) AF: 0.165 AC: 6838 AN: 41454

American (AMR) AF: 0.187 AC: 2856 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1025 AN: 3470

East Asian (EAS) AF: 0.235 AC: 1216 AN: 5170

South Asian (SAS) AF: 0.244 AC: 1174 AN: 4818

European-Finnish (FIN) AF: 0.235 AC: 2484 AN: 10556

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.281 AC: 19092 AN: 67950

Other (OTH) AF: 0.271 AC: 573 AN: 2112

Alfa AF: 0.269 Hom.: 17714

Bravo AF: 0.228

Asia WGS AF: 0.268 AC: 934 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Xeroderma pigmentosum, group F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.66
PhyloP100		-0.50
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: rs4781563; hg19: chr16-14045399;