rs2230009

Variant names:

• chr8-31064419-G-A
• rs2230009
• NM_000553.6:c.340G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31064419-G-A
• chr8-31064419-G-C
• chr8-31064419-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.340G>A​(p.Val114Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,613,308 control chromosomes in the GnomAD database, including 3,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V114L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.076 (499 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3073 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.0360
• Publications: 49 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• 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 (MetaRNN=0.0013432503).
• BP6: Variant 8-31064419-G-A is Benign according to our data. Variant chr8-31064419-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.340G>A	p.Val114Ile	missense	Exon 4 of 35	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.340G>A	p.Val114Ile	missense	Exon 4 of 35	ENSP00000298139.5
	WRN	ENST00000966176.1		c.340G>A	p.Val114Ile	missense	Exon 4 of 35	ENSP00000636235.1
	WRN	ENST00000860283.1		c.340G>A	p.Val114Ile	missense	Exon 4 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11592 AN: 152008 Hom.: 498 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0425

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0800

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.0690

GnomAD2 exomes AF: 0.0580 AC: 14588 AN: 251402 AF XY: 0.0583

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.0216

Gnomad FIN exome AF: 0.0682

Gnomad NFE exome AF: 0.0580

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0618 AC: 90271 AN: 1461182 Hom.: 3073 Cov.: 31 AF XY: 0.0623 AC XY: 45264 AN XY: 726884

African (AFR) AF: 0.127 AC: 4253 AN: 33472

American (AMR) AF: 0.0277 AC: 1241 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 1168 AN: 26130

East Asian (EAS) AF: 0.0232 AC: 921 AN: 39668

South Asian (SAS) AF: 0.0755 AC: 6514 AN: 86238

European-Finnish (FIN) AF: 0.0664 AC: 3547 AN: 53414

Middle Eastern (MID) AF: 0.0633 AC: 365 AN: 5766

European-Non Finnish (NFE) AF: 0.0617 AC: 68592 AN: 1111404

Other (OTH) AF: 0.0608 AC: 3670 AN: 60368

GnomAD4 genome AF: 0.0763 AC: 11605 AN: 152126 Hom.: 499 Cov.: 33 AF XY: 0.0749 AC XY: 5570 AN XY: 74372

African (AFR) AF: 0.125 AC: 5205 AN: 41480

American (AMR) AF: 0.0424 AC: 648 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 157 AN: 3466

East Asian (EAS) AF: 0.0240 AC: 124 AN: 5174

South Asian (SAS) AF: 0.0802 AC: 387 AN: 4824

European-Finnish (FIN) AF: 0.0696 AC: 736 AN: 10576

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

European-Non Finnish (NFE) AF: 0.0602 AC: 4094 AN: 68012

Other (OTH) AF: 0.0692 AC: 146 AN: 2110

Alfa AF: 0.0620 Hom.: 1598

Bravo AF: 0.0757

TwinsUK AF: 0.0626 AC: 232

ALSPAC AF: 0.0664 AC: 256

ESP6500AA AF: 0.125 AC: 551

ESP6500EA AF: 0.0564 AC: 485

ExAC AF: 0.0600 AC: 7282

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.8
DANN	Benign	0.33
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N
PhyloP100		0.036
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.020
MPC		0.055
ClinPred		0.00050	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.025
gMVP		0.34
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2230009; hg19: chr8-30921935; COSMIC: COSV53297589;