chr8-31076283-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000553.6(WRN):c.835C>T(p.Arg279Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,611,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.27

Publications

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

BP4

Computational evidence support a benign effect (MetaRNN=0.16207594).

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.835C>T	p.Arg279Trp	missense	Exon 8 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.835C>T	p.Arg279Trp	missense	Exon 8 of 35	ENSP00000298139.5	Q14191
WRN	ENST00000966176.1		c.835C>T	p.Arg279Trp	missense	Exon 8 of 35	ENSP00000636235.1
WRN	ENST00000860283.1		c.835C>T	p.Arg279Trp	missense	Exon 8 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151670

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000837

AC:

AN:

250824

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1459326

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726108

show subpopulations

African (AFR)

AF:

0.000479

AC:

AN:

33404

American (AMR)

AF:

0.000268

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.000177

AC:

AN:

39594

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000901

AC:

AN:

1109972

Other (OTH)

AF:

0.0000166

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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:

0.000138

AC:

AN:

151788

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.000411

AC:

AN:

41392

American (AMR)

AF:

0.000131

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000294

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Werner syndrome (4)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

0.16

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.83

M_CAP

Benign

0.022

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

2.3

PrimateAI

Benign

0.23

PROVEAN

Benign

-2.0

REVEL

Benign

0.066

Sift

Uncertain

0.011

Sift4G

Uncertain

0.018

Polyphen

0.99

Vest4

0.21

MVP

0.76

MPC

0.15

ClinPred

0.051

GERP RS

4.0

Varity_R

0.10

gMVP

0.33

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

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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