chr8-31173019-C-T

Position:

chr8-31173019-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 1.33

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:

WRN (HGNC:):

WRN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Likely_benign=2, Uncertain_significance=1, not_provided=1, Benign=6}. 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/exons	MANE	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.4216C>T	p.Arg1406*	stop_gained	35/35	ENST00000298139.7	NP_000544.2	Q14191
WRN	XM_011544639.4 linkuse as main transcript	c.4135C>T	p.Arg1379*	stop_gained	34/34		XP_011542941.1
WRN	XM_011544640.2 linkuse as main transcript	c.2617C>T	p.Arg873*	stop_gained	23/23		XP_011542942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.4216C>T	p.Arg1406*	stop_gained	35/35	1	NM_000553.6	ENSP00000298139.5		Q14191

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

152072

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00378

AC XY:

513

AN XY:

135656

show subpopulations

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.:

Cov.:

AF XY:

0.00274

AC XY:

1991

AN XY:

727084

show subpopulations

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.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74400

show subpopulations

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.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00342

AC:

415

Asia WGS

AF:

0.00867

AC:

AN:

3476

EpiCase

AF:

0.00142

EpiControl

AF:

0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	This variant is associated with the following publications: (PMID: 25619955, 26822949, 27153395, 27667302, 28125075) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	WRN: BS1, BS2 -

Werner syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2022	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2014	- -

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_addAF

Uncertain

0.042

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.17

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.35

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

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