rs4987239

Variant names:

• chr8-31064454-A-T
• rs4987239
• NM_000553.6:c.355+20A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.355+20A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.057 in 1,612,694 control chromosomes in the GnomAD database, including 2,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (184 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2742 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.140
• Publications: 4 publications found

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN Gene-Disease associations (from GenCC):

• Werner syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-31064454-A-T is Benign according to our data. Variant chr8-31064454-A-T is described in ClinVar as Benign. ClinVar VariationId is 256709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0732 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. 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
	WRN	NM_000553.6	MANE Select	c.355+20A>T		intron	N/A	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.355+20A>T		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.355+20A>T		intron	N/A	ENSP00000636235.1
	WRN	ENST00000860283.1		c.355+20A>T		intron	N/A	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6804 AN: 152122 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0496 AC: 12456 AN: 251284 AF XY: 0.0519

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0682

Gnomad NFE exome AF: 0.0576

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0583 AC: 85146 AN: 1460454 Hom.: 2742 Cov.: 31 AF XY: 0.0592 AC XY: 42992 AN XY: 726572

African (AFR) AF: 0.0141 AC: 472 AN: 33470

American (AMR) AF: 0.0213 AC: 951 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 1160 AN: 26116

East Asian (EAS) AF: 0.0231 AC: 916 AN: 39638

South Asian (SAS) AF: 0.0752 AC: 6480 AN: 86220

European-Finnish (FIN) AF: 0.0664 AC: 3544 AN: 53400

Middle Eastern (MID) AF: 0.0554 AC: 319 AN: 5762

European-Non Finnish (NFE) AF: 0.0613 AC: 68084 AN: 1110786

Other (OTH) AF: 0.0534 AC: 3220 AN: 60346

GnomAD4 genome AF: 0.0447 AC: 6806 AN: 152240 Hom.: 184 Cov.: 33 AF XY: 0.0451 AC XY: 3358 AN XY: 74442

African (AFR) AF: 0.0166 AC: 691 AN: 41536

American (AMR) AF: 0.0305 AC: 466 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5188

South Asian (SAS) AF: 0.0798 AC: 385 AN: 4826

European-Finnish (FIN) AF: 0.0695 AC: 736 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0596 AC: 4056 AN: 68018

Other (OTH) AF: 0.0432 AC: 91 AN: 2108

Alfa AF: 0.0508 Hom.: 35

Bravo AF: 0.0394

Asia WGS AF: 0.0550 AC: 191 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Werner syndrome (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.54
PhyloP100		-0.14
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: rs4987239; hg19: chr8-30921970;