NM_000553.6:c.970A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000553.6(WRN):c.970A>G(p.Thr324Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,614,046 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. T324I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 30 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -1.50

Publications

19 publications found

Variant links:

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

WRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0030954778).

BP6

Variant 8-31080997-A-G is Benign according to our data. Variant chr8-31080997-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00269 (410/152318) while in subpopulation SAS AF = 0.00849 (41/4828). AF 95% confidence interval is 0.00643. There are 2 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.970A>G	p.Thr324Ala	missense	Exon 9 of 35	NP_000544.2	Q14191

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
WRN	ENST00000298139.7	TSL:1 MANE Select	c.970A>G	p.Thr324Ala	missense	Exon 9 of 35	ENSP00000298139.5	Q14191
WRN	ENST00000966176.1		c.970A>G	p.Thr324Ala	missense	Exon 9 of 35	ENSP00000636235.1
WRN	ENST00000860283.1		c.970A>G	p.Thr324Ala	missense	Exon 9 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

410

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00357

AC:

897

AN:

251292

AF XY:

0.00415

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00419

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00337

AC:

4920

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2571

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33468

American (AMR)

AF:

0.00266

AC:

119

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39644

South Asian (SAS)

AF:

0.00903

AC:

779

AN:

86256

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00319

AC:

3551

AN:

1111942

Other (OTH)

AF:

0.00426

AC:

257

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

271

541

812

1082

1353

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00269

AC:

410

AN:

152318

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41574

American (AMR)

AF:

0.00333

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00849

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00381

AC:

259

AN:

68016

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00294

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00359

AC:

436

Asia WGS

AF:

0.00347

AC:

AN:

3476

EpiCase

AF:

0.00518

EpiControl

AF:

0.00628

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Werner syndrome (4)

not specified (3)

Malignant tumor of breast (1)

Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.024

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.10

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.31

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.075

PhyloP100

-1.5

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.85

REVEL

Benign

0.018

Sift

Benign

0.36

Sift4G

Benign

0.43

Polyphen

0.0030

Vest4

0.026

MVP

0.21

MPC

0.064

ClinPred

0.0053

GERP RS

-6.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.022

gMVP

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over