8-31059163-G-A

Position:

chr8-31059163-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1

The NM_000553.6(WRN):c.107G>A(p.Arg36Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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. R36W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.20

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 8-31059163-G-A is Benign according to our data. Variant chr8-31059163-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135432.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000867 (132/152270) while in subpopulation AFR AF= 0.00318 (132/41556). AF 95% confidence interval is 0.00274. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.107G>A	p.Arg36Gln	missense_variant	3/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.107G>A	p.Arg36Gln	missense_variant	3/35	1	NM_000553.6	P1
WRN	ENST00000650667.1 linkuse as main transcript	c.107G>A	p.Arg36Gln	missense_variant, NMD_transcript_variant	3/34

Frequencies

GnomAD3 genomes

AF:

0.000868

AC:

132

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

251318

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000760

AC:

111

AN:

1461200

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000867

AC:

132

AN:

152270

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00318

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.000797

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	This variant is associated with the following publications: (PMID: 24728327) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -

Werner syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Wiskott-Aldrich syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

WRN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.043

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.62

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.20

PROVEAN

Benign

0.15

REVEL

Benign

0.023

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MVP

0.32

MPC

0.073

ClinPred

0.0012

GERP RS

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 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