8-31058472-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000553.6(WRN):c.25A>G(p.Thr9Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0530

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06409302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.25A>G	p.Thr9Ala	missense_variant	Exon 2 of 35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 link	c.25A>G	p.Thr9Ala	missense_variant	Exon 2 of 35	1	NM_000553.6	ENSP00000298139.5		Q14191
WRN	ENST00000650667.1 link	n.25A>G		non_coding_transcript_exon_variant	Exon 2 of 34			ENSP00000498593.1		A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250838

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461410

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111792

Other (OTH)

AF:

0.0000166

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Werner syndrome

Uncertain:2

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 9 of the WRN protein (p.Thr9Ala). This variant is present in population databases (rs757791580, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 458425). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.64

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.11

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.23

M_CAP

Benign

0.0038

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.053

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.97

REVEL

Benign

0.025

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.0060

Vest4

0.12

MVP

0.34

MPC

0.065

ClinPred

0.012

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.64

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

8-31058472-A-G

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