NM_000553.6:c.3222G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000553.6(WRN):c.3222G>T(p.Leu1074Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,612,852 control chromosomes in the GnomAD database, including 166,265 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1074L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.46 ( 16580 hom., cov: 31)

Exomes 𝑓: 0.45 ( 149685 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.235

Publications

73 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
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=6.2455006E-6).

BP6

Variant 8-31141764-G-T is Benign according to our data. Variant chr8-31141764-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130759.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.3222G>T	p.Leu1074Phe	missense_variant	Exon 26 of 35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.3222G>T	p.Leu1074Phe	missense_variant	Exon 26 of 35	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 link	n.1855G>T		non_coding_transcript_exon_variant	Exon 14 of 23	1
WRN	ENST00000650667.1 link	n.*2836G>T		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000498593.1	A0A494C0M3
WRN	ENST00000650667.1 link	n.*2836G>T		3_prime_UTR_variant	Exon 25 of 34			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70066

AN:

151798

Hom.:

16551

Cov.:

show subpopulations

Gnomad AFR

AF:

0.486

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.543

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.617

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.360

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.445

Gnomad OTH

AF:

0.463

GnomAD2 exomes

AF:

0.455

AC:

114051

AN:

250884

AF XY:

0.445

show subpopulations

Gnomad AFR exome

AF:

0.488

Gnomad AMR exome

AF:

0.559

Gnomad ASJ exome

AF:

0.447

Gnomad EAS exome

AF:

0.640

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.442

Gnomad OTH exome

AF:

0.448

GnomAD4 exome

AF:

0.449

AC:

656181

AN:

1460936

Hom.:

149685

Cov.:

AF XY:

0.444

AC XY:

322859

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.491

AC:

16437

AN:

33458

American (AMR)

AF:

0.557

AC:

24883

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.444

AC:

11605

AN:

26130

East Asian (EAS)

AF:

0.606

AC:

24037

AN:

39680

South Asian (SAS)

AF:

0.332

AC:

28601

AN:

86216

European-Finnish (FIN)

AF:

0.364

AC:

19431

AN:

53384

Middle Eastern (MID)

AF:

0.369

AC:

2078

AN:

5636

European-Non Finnish (NFE)

AF:

0.452

AC:

501827

AN:

1111368

Other (OTH)

AF:

0.452

AC:

27282

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

18561

37122

55682

74243

92804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15224

30448

45672

60896

76120

<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:

0.462

AC:

70148

AN:

151916

Hom.:

16580

Cov.:

AF XY:

0.457

AC XY:

33967

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.486

AC:

20146

AN:

41416

American (AMR)

AF:

0.544

AC:

8303

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.454

AC:

1573

AN:

3466

East Asian (EAS)

AF:

0.618

AC:

3189

AN:

5164

South Asian (SAS)

AF:

0.319

AC:

1536

AN:

4810

European-Finnish (FIN)

AF:

0.360

AC:

3791

AN:

10530

Middle Eastern (MID)

AF:

0.483

AC:

140

AN:

290

European-Non Finnish (NFE)

AF:

0.445

AC:

30235

AN:

67948

Other (OTH)

AF:

0.464

AC:

978

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1913

3826

5738

7651

9564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.454

Hom.:

31162

Bravo

AF:

0.481

TwinsUK

AF:

0.463

AC:

1717

ALSPAC

AF:

0.455

AC:

1754

ESP6500AA

AF:

0.482

AC:

2124

ESP6500EA

AF:

0.459

AC:

3949

ExAC

AF:

0.449

AC:

54519

Asia WGS

AF:

0.480

AC:

1665

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5Other:1

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Werner syndrome

Benign:4

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Wiskott-Aldrich syndrome

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.7

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.049

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.070

MetaRNN

Benign

0.0000062

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.2

PhyloP100

0.23

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.020

REVEL

Benign

0.023

Sift

Benign

0.76

Sift4G

Benign

0.78

Polyphen

0.0

Vest4

0.0090

MutPred

0.29

Gain of methylation at K1073 (P = 0.0367);

MPC

0.069

ClinPred

0.0033

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over