rs3087424

Variant names:

• chr8-31147050-T-C
• rs3087424
• NM_000553.6:c.3384-3T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000553.6(WRN):​c.3384-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,608,544 control chromosomes in the GnomAD database, including 88 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 0.013 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (45 hom.)
• Consequence: WRN NM_000553.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002675
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.979

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 8-31147050-T-C is Benign according to our data. Variant chr8-31147050-T-C is described in ClinVar as [Benign]. Clinvar id is 238152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1931/152302) while in subpopulation AFR AF= 0.0438 (1822/41558). AF 95% confidence interval is 0.0422. There are 43 homozygotes in gnomad4. There are 877 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.3384-3T>C		splice_region_variant, intron_variant	Intron 28 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.3384-3T>C		splice_region_variant, intron_variant	Intron 28 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.2017-3T>C		splice_region_variant, intron_variant	Intron 16 of 22	1
WRN	ENST00000650667.1	n.*2998-3T>C		splice_region_variant, intron_variant	Intron 27 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1924 AN: 152184 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0438

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00315 AC: 786 AN: 249752 Hom.: 18 AF XY: 0.00217 AC XY: 294 AN XY: 135288

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00131 AC: 1912 AN: 1456242 Hom.: 45 Cov.: 30 AF XY: 0.00116 AC XY: 837 AN XY: 724354

Gnomad4 AFR exome AF: 0.0484

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000822

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000361

Gnomad4 OTH exome AF: 0.00261

GnomAD4 genome AF: 0.0127 AC: 1931 AN: 152302 Hom.: 43 Cov.: 33 AF XY: 0.0118 AC XY: 877 AN XY: 74472

Gnomad4 AFR AF: 0.0438

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00339 Hom.: 9

Bravo AF: 0.0141

Asia WGS AF: 0.00231 AC: 8 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:4

Jan 13, 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. -

Jan 28, 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:1

Aug 17, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WRN-related disorder Benign:1

Aug 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.25
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

Other links and lift over

dbSNP: rs3087424; hg19: chr8-31004566;