8-31081208-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000553.6(WRN):c.1181C>T(p.Ser394Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S394W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 2.33

Publications

2 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027703822).

BP6

Variant 8-31081208-C-T is Benign according to our data. Variant chr8-31081208-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 412710.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000122 (179/1461510) while in subpopulation AMR AF = 0.00324 (145/44692). AF 95% confidence interval is 0.00281. There are 0 homozygotes in GnomAdExome4. There are 75 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1181C>T	p.Ser394Leu	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.1181C>T	p.Ser394Leu	missense	Exon 9 of 35	ENSP00000298139.5	Q14191
WRN	ENST00000966176.1		c.1181C>T	p.Ser394Leu	missense	Exon 9 of 35	ENSP00000636235.1
WRN	ENST00000860283.1		c.1181C>T	p.Ser394Leu	missense	Exon 9 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000563

AC:

141

AN:

250450

AF XY:

0.000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000122

AC:

179

AN:

1461510

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00324

AC:

145

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1111838

Other (OTH)

AF:

0.0000663

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000125

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41416

American (AMR)

AF:

0.000983

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000408

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Werner syndrome (3)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.019

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.6

PhyloP100

2.3

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.19

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.010

Polyphen

0.99

Vest4

0.54

MVP

0.81

MPC

0.29

ClinPred

0.11

GERP RS

4.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.13

gMVP

0.22

Mutation Taster

=84/16

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over