chr8-31167003-G-GT

Variant names:

• chr8-31167003-G-GT
• rs368931913
• NM_000553.6:c.3983-12dupT

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.3983-12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,601,232 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.450
• Publications: 0 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

ENSG00000253961 (HGNC:58431):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-31167003-G-GT is Benign according to our data. Variant chr8-31167003-G-GT is described in ClinVar as Benign. ClinVar VariationId is 256710.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 = 0.00461 (702/152204) while in subpopulation AFR AF = 0.0159 (659/41542). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.3983-12dupT		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.3983-19_3983-18insT		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.2616-19_2616-18insT		intron	N/A
	WRN	ENST00000966176.1		c.3998-19_3998-18insT		intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.00460 AC: 700 AN: 152086 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00128 AC: 317 AN: 247234 AF XY: 0.000956

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.0000716

Gnomad OTH exome AF: 0.000835

GnomAD4 exome AF: 0.000549 AC: 796 AN: 1449028 Hom.: 7 Cov.: 28 AF XY: 0.000470 AC XY: 339 AN XY: 721368

African (AFR) AF: 0.0150 AC: 497 AN: 33074

American (AMR) AF: 0.00147 AC: 65 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25946

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39542

South Asian (SAS) AF: 0.000257 AC: 22 AN: 85450

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53236

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5722

European-Non Finnish (NFE) AF: 0.000115 AC: 127 AN: 1101906

Other (OTH) AF: 0.00115 AC: 69 AN: 59898

GnomAD4 genome AF: 0.00461 AC: 702 AN: 152204 Hom.: 6 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74422

African (AFR) AF: 0.0159 AC: 659 AN: 41542

American (AMR) AF: 0.00144 AC: 22 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67986

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000632 Hom.: 0

Bravo AF: 0.00536

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Werner syndrome (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

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: rs368931913; hg19: chr8-31024519; COSMIC: COSV53307301; COSMIC: COSV53307301;