rs11574410

Variant names:

• chr8-31173019-C-T
• rs11574410
• NM_000553.6:c.4216C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The NM_000553.6(WRN):​c.4216C>T​(p.Arg1406*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,806 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (31 hom.)
• Consequence: WRN NM_000553.6 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: 1.33

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]

ENSG00000253961 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0193 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 8-31173019-C-T is Benign according to our data. Variant chr8-31173019-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135443.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=7, Likely_benign=2, not_provided=1}. Variant chr8-31173019-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00175 (267/152190) while in subpopulation SAS AF= 0.0197 (95/4824). AF 95% confidence interval is 0.0165. There are 2 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.4216C>T	p.Arg1406*	stop_gained	Exon 35 of 35	ENST00000298139.7	NP_000544.2
WRN	XM_011544639.4	c.4135C>T	p.Arg1379*	stop_gained	Exon 34 of 34		XP_011542941.1
WRN	XM_011544640.2	c.2617C>T	p.Arg873*	stop_gained	Exon 23 of 23		XP_011542942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.4216C>T	p.Arg1406*	stop_gained	Exon 35 of 35	1	NM_000553.6	ENSP00000298139.5

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152072 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00305 AC: 766 AN: 250856 Hom.: 10 AF XY: 0.00378 AC XY: 513 AN XY: 135656

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0170

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00229 AC: 3344 AN: 1461616 Hom.: 31 Cov.: 31 AF XY: 0.00274 AC XY: 1991 AN XY: 727084

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152190 Hom.: 2 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74400

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00141

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.00867 AC: 30 AN: 3476

EpiCase AF: 0.00142

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Werner syndrome Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:2

May 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25619955, 26822949, 27153395, 27667302, 28125075) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WRN: BS1, BS2 -

not specified Benign:2 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Dec 30, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: WRN c.4216C>T (p.Arg1406X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed or classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.0031 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the South Asian subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in WRN causing Werner Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.4216C>T in individuals affected with Werner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as benign/likely benign (n=4)(VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.17
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.35	N
Vest4		0.65
GERP RS		1.9

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

Other links and lift over

dbSNP: rs11574410; hg19: chr8-31030535; COSMIC: COSV104591475;