rs1800389

chr8-31067041-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000553.6(WRN):c.513C>T(p.Cys171=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,612,846 control chromosomes in the GnomAD database, including 407,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35116 hom., cov: 31)
  • Exomes 𝑓: 0.71 (372164 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.75

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-31067041-C-T is Benign according to our data. Variant chr8-31067041-C-T is described in ClinVar as [Benign]. Clinvar id is 130763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31067041-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WRN	NM_000553.6	c.513C>T	p.Cys171=	synonymous_variant	6/35	ENST00000298139.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WRN	ENST00000298139.7	c.513C>T	p.Cys171=	synonymous_variant	6/35	1	NM_000553.6	P1
WRN	ENST00000650667.1	c.*127C>T		3_prime_UTR_variant, NMD_transcript_variant	5/34

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102130 AN: 151854 Hom.: 35092 Cov.: 31

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.666

GnomAD3 exomes AF: 0.713 AC: 178921 AN: 251004 Hom.: 64567 AF XY: 0.711 AC XY: 96531 AN XY: 135684

Gnomad AFR exome AF: 0.528

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.740

Gnomad EAS exome AF: 0.865

Gnomad SAS exome AF: 0.659

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.712 AC: 1040462 AN: 1460874 Hom.: 372164 Cov.: 53 AF XY: 0.711 AC XY: 516406 AN XY: 726766

Gnomad4 AFR exome AF: 0.526

Gnomad4 AMR exome AF: 0.763

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.660

Gnomad4 FIN exome AF: 0.739

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.705

GnomAD4 genome AF: 0.672 AC: 102199 AN: 151972 Hom.: 35116 Cov.: 31 AF XY: 0.678 AC XY: 50329 AN XY: 74278

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.758

Gnomad4 ASJ AF: 0.738

Gnomad4 EAS AF: 0.864

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.755

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.668

Alfa AF: 0.694 Hom.: 24454

Bravo AF: 0.670

Asia WGS AF: 0.764 AC: 2657 AN: 3478

EpiCase AF: 0.701

EpiControl AF: 0.703

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Werner syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.3
Dann	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1800389; hg19: chr8-30924557;