rs4733224

Variant names:

• chr8-31109853-T-C
• rs4733224
• NM_000553.6:c.2089-1762T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000553.6(WRN):​c.2089-1762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 151,960 control chromosomes in the GnomAD database, including 8,646 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (8646 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6	c.2089-1762T>C		intron_variant	Intron 18 of 34	ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.2089-1762T>C		intron_variant	Intron 18 of 34	1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.722-1762T>C		intron_variant	Intron 6 of 22	1
WRN	ENST00000650667.1	n.*1703-1762T>C		intron_variant	Intron 17 of 33			ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50144 AN: 151842 Hom.: 8636 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.329

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.330 AC: 50174 AN: 151960 Hom.: 8646 Cov.: 32 AF XY: 0.334 AC XY: 24837 AN XY: 74280

African (AFR) AF: 0.258 AC: 10694 AN: 41458

American (AMR) AF: 0.296 AC: 4521 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3468

East Asian (EAS) AF: 0.291 AC: 1504 AN: 5170

South Asian (SAS) AF: 0.418 AC: 2013 AN: 4814

European-Finnish (FIN) AF: 0.435 AC: 4584 AN: 10550

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24321 AN: 67906

Other (OTH) AF: 0.330 AC: 697 AN: 2114

Alfa AF: 0.350 Hom.: 15770

Bravo AF: 0.314

Asia WGS AF: 0.354 AC: 1231 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.61
DANN	Benign	0.73
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs4733224; hg19: chr8-30967369; COSMIC: COSV53308559;