chr8-31064419-G-A

Position:

• chr8-31064419-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.340G>A​(p.Val114Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0631 in 1,613,308 control chromosomes in the GnomAD database, including 3,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (499 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3073 hom.)
• Consequence: WRN NM_000553.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.0360

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013432503).
• BP6: Variant 8-31064419-G-A is Benign according to our data. Variant chr8-31064419-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31064419-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.340G>A	p.Val114Ile	missense_variant	4/35	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.340G>A	p.Val114Ile	missense_variant	4/35	1	NM_000553.6	ENSP00000298139	P1
WRN	ENST00000650667.1	c.210-496G>A		intron_variant, NMD_transcript_variant				ENSP00000498593

Frequencies

GnomAD3 genomes AF: 0.0763 AC: 11592 AN: 152008 Hom.: 498 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0425

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0800

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.0690

GnomAD3 exomes AF: 0.0580 AC: 14588 AN: 251402 Hom.: 554 AF XY: 0.0583 AC XY: 7917 AN XY: 135892

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.0216

Gnomad SAS exome AF: 0.0780

Gnomad FIN exome AF: 0.0682

Gnomad NFE exome AF: 0.0580

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0618 AC: 90271 AN: 1461182 Hom.: 3073 Cov.: 31 AF XY: 0.0623 AC XY: 45264 AN XY: 726884

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.0277

Gnomad4 ASJ exome AF: 0.0447

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0755

Gnomad4 FIN exome AF: 0.0664

Gnomad4 NFE exome AF: 0.0617

Gnomad4 OTH exome AF: 0.0608

GnomAD4 genome AF: 0.0763 AC: 11605 AN: 152126 Hom.: 499 Cov.: 33 AF XY: 0.0749 AC XY: 5570 AN XY: 74372

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0424

Gnomad4 ASJ AF: 0.0453

Gnomad4 EAS AF: 0.0240

Gnomad4 SAS AF: 0.0802

Gnomad4 FIN AF: 0.0696

Gnomad4 NFE AF: 0.0602

Gnomad4 OTH AF: 0.0692

Alfa AF: 0.0582 Hom.: 753

Bravo AF: 0.0757

TwinsUK AF: 0.0626 AC: 232

ALSPAC AF: 0.0664 AC: 256

ESP6500AA AF: 0.125 AC: 551

ESP6500EA AF: 0.0564 AC: 485

ExAC AF: 0.0600 AC: 7282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Werner syndrome Benign:3

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	This variant is associated with the following publications: (PMID: 25637295, 27153395, 17764108, 24728327, 23523974) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wiskott-Aldrich syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.8
DANN	Benign	0.33
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.44	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.020
MPC		0.055
ClinPred		0.00050	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.025
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs2230009; hg19: chr8-30921935; COSMIC: COSV53297589;