rs3087409

Variant names:

• chr8-31088887-C-A
• rs3087409
• NM_000553.6:c.1577-3C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31088887-C-A
• chr8-31088887-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.1577-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,607,294 control chromosomes in the GnomAD database, including 3,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (509 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3036 hom.)
• Consequence: WRN NM_000553.6 splice_region, intron
• Scores: Splicing: ADA: 0.3898
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.54
• Publications: 17 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 8-31088887-C-A is Benign according to our data. Variant chr8-31088887-C-A is described in ClinVar as Benign. ClinVar VariationId is 130753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 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.1577-3C>A		splice_region 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.1577-3C>A		splice_region intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.278-3C>A		splice_region intron	N/A
	WRN	ENST00000966176.1		c.1577-3C>A		splice_region intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.0769 AC: 11674 AN: 151838 Hom.: 508 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.0697

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0686

GnomAD2 exomes AF: 0.0566 AC: 13833 AN: 244582 AF XY: 0.0566

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0252

Gnomad ASJ exome AF: 0.0435

Gnomad EAS exome AF: 0.0208

Gnomad FIN exome AF: 0.0679

Gnomad NFE exome AF: 0.0561

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0616 AC: 89699 AN: 1455338 Hom.: 3036 Cov.: 31 AF XY: 0.0621 AC XY: 44901 AN XY: 723534

African (AFR) AF: 0.129 AC: 4310 AN: 33364

American (AMR) AF: 0.0275 AC: 1218 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 1157 AN: 25956

East Asian (EAS) AF: 0.0231 AC: 914 AN: 39556

South Asian (SAS) AF: 0.0737 AC: 6280 AN: 85262

European-Finnish (FIN) AF: 0.0662 AC: 3512 AN: 53034

Middle Eastern (MID) AF: 0.0618 AC: 338 AN: 5466

European-Non Finnish (NFE) AF: 0.0616 AC: 68316 AN: 1108320

Other (OTH) AF: 0.0608 AC: 3654 AN: 60052

GnomAD4 genome AF: 0.0770 AC: 11694 AN: 151956 Hom.: 509 Cov.: 32 AF XY: 0.0756 AC XY: 5616 AN XY: 74282

African (AFR) AF: 0.128 AC: 5322 AN: 41452

American (AMR) AF: 0.0423 AC: 646 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 157 AN: 3464

East Asian (EAS) AF: 0.0237 AC: 123 AN: 5184

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

European-Finnish (FIN) AF: 0.0697 AC: 737 AN: 10572

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0600 AC: 4071 AN: 67884

Other (OTH) AF: 0.0688 AC: 145 AN: 2108

Alfa AF: 0.0634 Hom.: 1475

Bravo AF: 0.0765

Asia WGS AF: 0.0620 AC: 216 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Werner syndrome (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.73
PhyloP100		1.5
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.39
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.050		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: rs3087409; hg19: chr8-30946403;