dbSNP rs201643901: WRN:p.Ile283Leu (chr8-31080874-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_000553.6(WRN):c.847A>C(p.Ile283Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. I283V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.70

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: 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=0.046186984).

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.847A>C	p.Ile283Leu	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.847A>C	p.Ile283Leu	missense	Exon 9 of 35	ENSP00000298139.5	Q14191
WRN	ENST00000966176.1		c.847A>C	p.Ile283Leu	missense	Exon 9 of 35	ENSP00000636235.1
WRN	ENST00000860283.1		c.847A>C	p.Ile283Leu	missense	Exon 9 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722094

African (AFR)

AF:

0.00

AC:

AN:

32800

American (AMR)

AF:

0.00

AC:

AN:

43008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25764

East Asian (EAS)

AF:

0.00

AC:

AN:

39584

South Asian (SAS)

AF:

0.00

AC:

AN:

83806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5168

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108842

Other (OTH)

AF:

0.00

AC:

AN:

59924

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Werner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.064

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.050

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.44

M_CAP

Benign

0.0023

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

PhyloP100

-1.7

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.33

REVEL

Benign

0.038

Sift

Benign

0.43

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.13

MutPred

0.29

Loss of ubiquitination at K286 (P = 0.0787)

MVP

0.20

MPC

0.064

ClinPred

0.16

GERP RS

-12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.040

gMVP

0.14

Mutation Taster

=86/14

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over