NM_000553.6:c.513C>T

Variant names:

• chr8-31067041-C-T
• rs1800389
• NM_000553.6:c.513C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000553.6(WRN):​c.513C>T​(p.Cys171Cys) 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:11
• Conservation: PhyloP100: 1.75
• Publications: 32 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.513C>T	p.Cys171Cys	synonymous	Exon 6 of 35	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.513C>T	p.Cys171Cys	synonymous	Exon 6 of 35	ENSP00000298139.5
	WRN	ENST00000650667.1		n.*127C>T		non_coding_transcript_exon	Exon 5 of 34	ENSP00000498593.1
	WRN	ENST00000650667.1		n.*127C>T		3_prime_UTR	Exon 5 of 34	ENSP00000498593.1

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

GnomAD2 exomes AF: 0.713 AC: 178921 AN: 251004 AF XY: 0.711

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 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

African (AFR) AF: 0.526 AC: 17598 AN: 33446

American (AMR) AF: 0.763 AC: 34099 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 19224 AN: 26116

East Asian (EAS) AF: 0.875 AC: 34684 AN: 39632

South Asian (SAS) AF: 0.660 AC: 56908 AN: 86230

European-Finnish (FIN) AF: 0.739 AC: 39324 AN: 53208

Middle Eastern (MID) AF: 0.661 AC: 3811 AN: 5764

European-Non Finnish (NFE) AF: 0.713 AC: 792286 AN: 1111400

Other (OTH) AF: 0.705 AC: 42528 AN: 60364

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

African (AFR) AF: 0.530 AC: 21940 AN: 41392

American (AMR) AF: 0.758 AC: 11574 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2563 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4469 AN: 5170

South Asian (SAS) AF: 0.660 AC: 3181 AN: 4822

European-Finnish (FIN) AF: 0.755 AC: 7963 AN: 10554

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48202 AN: 67968

Other (OTH) AF: 0.668 AC: 1413 AN: 2114

Alfa AF: 0.691 Hom.: 32303

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 21, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Werner syndrome Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.3
DANN	Benign	0.43
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800389; hg19: chr8-30924557; COSMIC: COSV108141453;