rs3213199

Variant names:

• chr8-31108475-T-A
• rs3213199
• NM_000553.6:c.2089-3140T>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31108475-T-A
• chr8-31108475-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000553.6(WRN):​c.2089-3140T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 151,670 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1507 hom., cov: 32)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63
• 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: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-31108475-T-A is Benign according to our data. Variant chr8-31108475-T-A is described in ClinVar as Benign. ClinVar VariationId is 1289082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.2089-3140T>A		intron	N/A	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.2089-3140T>A		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.722-3140T>A		intron	N/A
	WRN	ENST00000966176.1		c.2089-3125T>A		intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19201 AN: 151550 Hom.: 1506 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0719

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.127 AC: 19214 AN: 151670 Hom.: 1507 Cov.: 32 AF XY: 0.127 AC XY: 9452 AN XY: 74170

African (AFR) AF: 0.0354 AC: 1453 AN: 41056

American (AMR) AF: 0.128 AC: 1961 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 596 AN: 3470

East Asian (EAS) AF: 0.0717 AC: 371 AN: 5176

South Asian (SAS) AF: 0.173 AC: 833 AN: 4820

European-Finnish (FIN) AF: 0.177 AC: 1868 AN: 10544

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11696 AN: 68012

Other (OTH) AF: 0.129 AC: 271 AN: 2104

Alfa AF: 0.0777 Hom.: 109

Bravo AF: 0.117

Asia WGS AF: 0.110 AC: 382 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.047
DANN	Benign	0.55
PhyloP100		-1.6
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: rs3213199; hg19: chr8-30965991;