rs180814740

Positions:

chr8-31111654-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000553.6(WRN):c.2128A>G(p.Ile710Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.42

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030443132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.2128A>G	p.Ile710Val	missense_variant	19/35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.2128A>G	p.Ile710Val	missense_variant	19/35	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 link	n.761A>G		non_coding_transcript_exon_variant	7/23	1
WRN	ENST00000650667.1 link	n.*1742A>G		non_coding_transcript_exon_variant	18/34			ENSP00000498593.1	A0A494C0M3
WRN	ENST00000650667.1 link	n.*1742A>G		3_prime_UTR_variant	18/34			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251400

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000816

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Werner syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 710 of the WRN protein (p.Ile710Val). This variant is present in population databases (rs180814740, gnomAD 0.08%). 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: 362805). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.2128A>G (p.I710V) alteration is located in exon 19 (coding exon 18) of the WRN gene. This alteration results from a A to G substitution at nucleotide position 2128, causing the isoleucine (I) at amino acid position 710 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Ovarian cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.1

DANN

Benign

0.49

DEOGEN2

Benign

0.073

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.76

M_CAP

Benign

0.012

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-2.2

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.15

REVEL

Benign

0.051

Sift

Benign

0.61

Sift4G

Benign

0.74

Polyphen

0.031

Vest4

0.13

MVP

0.23

MPC

0.093

ClinPred

0.035

GERP RS

1.5

Varity_R

0.051

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over