8-31142496-T-C

Variant names:

• chr8-31142496-T-C
• rs2725364
• NM_000553.6:c.3234-130T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.3234-130T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 629,734 control chromosomes in the GnomAD database, including 45,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9590 hom., cov: 32)
  • Exomes 𝑓: 0.37 (35503 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.654
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-31142496-T-C is Benign according to our data. Variant chr8-31142496-T-C is described in ClinVar as Benign. ClinVar VariationId is 256708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.596 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.3234-130T>C		intron	N/A	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.3234-130T>C		intron	N/A	ENSP00000298139.5
	WRN	ENST00000521620.5	TSL:1	n.1867-130T>C		intron	N/A
	WRN	ENST00000650667.1		n.*2848-130T>C		intron	N/A	ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 52022 AN: 151910 Hom.: 9585 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.372 AC: 177714 AN: 477706 Hom.: 35503 AF XY: 0.370 AC XY: 89224 AN XY: 240838

African (AFR) AF: 0.224 AC: 2510 AN: 11222

American (AMR) AF: 0.455 AC: 4881 AN: 10732

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 4447 AN: 10840

East Asian (EAS) AF: 0.584 AC: 14342 AN: 24548

South Asian (SAS) AF: 0.260 AC: 4737 AN: 18192

European-Finnish (FIN) AF: 0.271 AC: 9236 AN: 34052

Middle Eastern (MID) AF: 0.311 AC: 539 AN: 1732

European-Non Finnish (NFE) AF: 0.374 AC: 128271 AN: 342864

Other (OTH) AF: 0.372 AC: 8751 AN: 23524

GnomAD4 genome AF: 0.342 AC: 52050 AN: 152028 Hom.: 9590 Cov.: 32 AF XY: 0.340 AC XY: 25292 AN XY: 74300

African (AFR) AF: 0.227 AC: 9421 AN: 41490

American (AMR) AF: 0.464 AC: 7081 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1496 AN: 3472

East Asian (EAS) AF: 0.614 AC: 3177 AN: 5176

South Asian (SAS) AF: 0.285 AC: 1374 AN: 4818

European-Finnish (FIN) AF: 0.276 AC: 2920 AN: 10574

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25443 AN: 67934

Other (OTH) AF: 0.368 AC: 777 AN: 2110

Alfa AF: 0.196 Hom.: 450

Bravo AF: 0.357

Asia WGS AF: 0.442 AC: 1534 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:2

Dec 05, 2021

Genome-Nilou Lab

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

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.85
CADD	Benign	0.28
DANN	Benign	0.77
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2725364; hg19: chr8-31000012; COSMIC: COSV53300364;