rs781741859

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000553.6(WRN):c.715A>C(p.Ile239Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,354 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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. I239V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.108

Publications

0 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=0.055822074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.715A>C	p.Ile239Leu	missense_variant	Exon 7 of 35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
WRN	ENST00000298139.7 link	c.715A>C	p.Ile239Leu	missense_variant	Exon 7 of 35	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000651642.1 link	c.10A>C	p.Ile4Leu	missense_variant	Exon 1 of 4			ENSP00000498779.1
WRN	ENST00000650667.1 link	n.*329A>C		non_coding_transcript_exon_variant	Exon 6 of 34			ENSP00000498593.1
WRN	ENST00000650667.1 link	n.*329A>C		3_prime_UTR_variant	Exon 6 of 34			ENSP00000498593.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000809

AC:

AN:

247106

AF XY:

0.0000150

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:

0.0000180

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453354

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33314

American (AMR)

AF:

0.00

AC:

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00

AC:

AN:

85834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105246

Other (OTH)

AF:

0.00

AC:

AN:

59982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.71

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.051

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.48

M_CAP

Benign

0.0035

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.11

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.21

REVEL

Benign

0.0060

Sift

Benign

1.0

Sift4G

Benign

0.82

Polyphen

0.0

Vest4

0.16

MutPred

0.29

Loss of methylation at K241 (P = 0.0588);

MVP

0.24

MPC

0.064

ClinPred

0.021

GERP RS

-1.8

PromoterAI

-0.0020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.044

gMVP

0.20

Mutation Taster

=96/4

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over