8-31076156-AT-A

Variant names:

• chr8-31076156-AT-A
• rs543830844
• NM_000553.6:c.725-9delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000553.6(WRN):​c.725-9delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,586,546 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.540
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 8-31076156-AT-A is Benign according to our data. Variant chr8-31076156-AT-A is described in ClinVar as Benign. ClinVar VariationId is 256711.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 = 0.00293 (446/152032) while in subpopulation AFR AF = 0.00981 (407/41470). AF 95% confidence interval is 0.00903. There are 2 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.725-9delT		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.725-16delT		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.725-16delT		intron	N/A	ENSP00000636235.1
	WRN	ENST00000860283.1		c.725-16delT		intron	N/A	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 445 AN: 151914 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000961 AC: 241 AN: 250686 AF XY: 0.000752

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000451 AC: 647 AN: 1434514 Hom.: 1 Cov.: 28 AF XY: 0.000435 AC XY: 311 AN XY: 715484

African (AFR) AF: 0.0103 AC: 340 AN: 32916

American (AMR) AF: 0.00116 AC: 52 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000809 AC: 21 AN: 25946

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39468

South Asian (SAS) AF: 0.0000933 AC: 8 AN: 85726

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53390

Middle Eastern (MID) AF: 0.000700 AC: 4 AN: 5718

European-Non Finnish (NFE) AF: 0.000142 AC: 154 AN: 1087196

Other (OTH) AF: 0.00103 AC: 61 AN: 59476

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152032 Hom.: 2 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74332

African (AFR) AF: 0.00981 AC: 407 AN: 41470

American (AMR) AF: 0.00105 AC: 16 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67980

Other (OTH) AF: 0.00143 AC: 3 AN: 2100

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.00353

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Werner syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

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: rs543830844; hg19: chr8-30933672; COSMIC: COSV53295695;