8-31141606-C-T

Position:

chr8-31141606-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000553.6(WRN):c.3138+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,613,698 control chromosomes in the GnomAD database, including 186,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 14117 hom., cov: 30)

Exomes 𝑓: 0.48 ( 172572 hom. )

Consequence

WRN
NM_000553.6 splice_region, intron

Scores

Splicing: ADA: 0.00008950

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0870

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 8-31141606-C-T is Benign according to our data. Variant chr8-31141606-C-T is described in ClinVar as [Benign]. Clinvar id is 130754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-31141606-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6 linkuse as main transcript	c.3138+6C>T		splice_region_variant, intron_variant		ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 linkuse as main transcript	c.3138+6C>T	splice_region_variant, intron_variant	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 linkuse as main transcript	n.1771+6C>T	splice_region_variant, intron_variant	1
WRN	ENST00000650667.1 linkuse as main transcript	n.*2752+6C>T	splice_region_variant, intron_variant			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61669

AN:

151764

Hom.:

14117

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.608

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.358

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.492

Gnomad OTH

AF:

0.423

GnomAD3 exomes

AF:

0.470

AC:

118232

AN:

251362

Hom.:

29186

AF XY:

0.483

AC XY:

65615

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.404

Gnomad ASJ exome

AF:

0.507

Gnomad EAS exome

AF:

0.338

Gnomad SAS exome

AF:

0.591

Gnomad FIN exome

AF:

0.567

Gnomad NFE exome

AF:

0.497

Gnomad OTH exome

AF:

0.491

GnomAD4 exome

AF:

0.481

AC:

703811

AN:

1461818

Hom.:

172572

Cov.:

AF XY:

0.487

AC XY:

353843

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.184

Gnomad4 AMR exome

AF:

0.404

Gnomad4 ASJ exome

AF:

0.509

Gnomad4 EAS exome

AF:

0.371

Gnomad4 SAS exome

AF:

0.585

Gnomad4 FIN exome

AF:

0.569

Gnomad4 NFE exome

AF:

0.485

Gnomad4 OTH exome

AF:

0.473

GnomAD4 genome

AF:

0.406

AC:

61670

AN:

151880

Hom.:

14117

Cov.:

AF XY:

0.412

AC XY:

30594

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.198

Gnomad4 AMR

AF:

0.392

Gnomad4 ASJ

AF:

0.499

Gnomad4 EAS

AF:

0.357

Gnomad4 SAS

AF:

0.595

Gnomad4 FIN

AF:

0.572

Gnomad4 NFE

AF:

0.492

Gnomad4 OTH

AF:

0.423

Alfa

AF:

0.467

Hom.:

15123

Bravo

AF:

0.379

Asia WGS

AF:

0.452

AC:

1572

AN:

3478

EpiCase

AF:

0.504

EpiControl

AF:

0.502

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Werner syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
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	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. -
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

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.4

DANN

Benign

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000090

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.0

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