rs2737335

Variant names:

• chr8-31141607-G-A
• rs2737335
• NM_000553.6:c.3138+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31141607-G-A
• chr8-31141607-G-C
• chr8-31141607-G-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.3138+7G>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 0.449 in 1,613,658 control chromosomes in the GnomAD database, including 165,330 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 0.46 (16495 hom., cov: 30)
  • Exomes 𝑓: 0.45 (148835 hom.)
• Consequence: WRN NM_000553.6 splice_region, intron
• Scores: Splicing: ADA: 0.00004241
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.618
• Publications: 15 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=-0.89).
• BP6: Variant 8-31141607-G-A is Benign according to our data. Variant chr8-31141607-G-A is described in ClinVar as Benign. ClinVar VariationId is 130755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.6 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.3138+7G>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.3138+7G>A		splice_region intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.1771+7G>A		splice_region intron	N/A
	WRN	ENST00000966176.1		c.3153+7G>A		splice_region intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69854 AN: 151726 Hom.: 16466 Cov.: 30

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.454 AC: 114078 AN: 251362 AF XY: 0.445

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.447

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.448 AC: 654666 AN: 1461814 Hom.: 148835 Cov.: 57 AF XY: 0.443 AC XY: 322115 AN XY: 727208

African (AFR) AF: 0.490 AC: 16407 AN: 33478

American (AMR) AF: 0.555 AC: 24814 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11595 AN: 26132

East Asian (EAS) AF: 0.606 AC: 24043 AN: 39692

South Asian (SAS) AF: 0.331 AC: 28578 AN: 86248

European-Finnish (FIN) AF: 0.364 AC: 19437 AN: 53410

Middle Eastern (MID) AF: 0.365 AC: 2106 AN: 5768

European-Non Finnish (NFE) AF: 0.450 AC: 500492 AN: 1111978

Other (OTH) AF: 0.450 AC: 27194 AN: 60388

GnomAD4 genome AF: 0.461 AC: 69937 AN: 151844 Hom.: 16495 Cov.: 30 AF XY: 0.456 AC XY: 33873 AN XY: 74216

African (AFR) AF: 0.486 AC: 20101 AN: 41390

American (AMR) AF: 0.542 AC: 8279 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1570 AN: 3470

East Asian (EAS) AF: 0.618 AC: 3181 AN: 5148

South Asian (SAS) AF: 0.319 AC: 1525 AN: 4788

European-Finnish (FIN) AF: 0.360 AC: 3803 AN: 10558

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30109 AN: 67906

Other (OTH) AF: 0.461 AC: 973 AN: 2110

Alfa AF: 0.449 Hom.: 8733

Bravo AF: 0.480

Asia WGS AF: 0.479 AC: 1664 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Werner syndrome (5)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.37
PhyloP100		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0
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: rs2737335; hg19: chr8-30999123;