rs1800389

Variant names:

• chr8-31067041-C-T
• rs1800389
• NM_000553.6:c.513C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000553.6(WRN):​c.513C>T​(p.Cys171Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,612,846 control chromosomes in the GnomAD database, including 407,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35116 hom., cov: 31)
  • Exomes 𝑓: 0.71 (372164 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.75
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-31067041-C-T is Benign according to our data. Variant chr8-31067041-C-T is described in ClinVar as Benign. ClinVar VariationId is 130763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 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.513C>T	p.Cys171Cys	synonymous	Exon 6 of 35	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.513C>T	p.Cys171Cys	synonymous	Exon 6 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.513C>T	p.Cys171Cys	synonymous	Exon 6 of 35	ENSP00000636235.1
	WRN	ENST00000860283.1		c.513C>T	p.Cys171Cys	synonymous	Exon 6 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102130 AN: 151854 Hom.: 35092 Cov.: 31

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.864

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.755

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.666

GnomAD2 exomes AF: 0.713 AC: 178921 AN: 251004 AF XY: 0.711

Gnomad AFR exome AF: 0.528

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.740

Gnomad EAS exome AF: 0.865

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.712 AC: 1040462 AN: 1460874 Hom.: 372164 Cov.: 53 AF XY: 0.711 AC XY: 516406 AN XY: 726766

African (AFR) AF: 0.526 AC: 17598 AN: 33446

American (AMR) AF: 0.763 AC: 34099 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 19224 AN: 26116

East Asian (EAS) AF: 0.875 AC: 34684 AN: 39632

South Asian (SAS) AF: 0.660 AC: 56908 AN: 86230

European-Finnish (FIN) AF: 0.739 AC: 39324 AN: 53208

Middle Eastern (MID) AF: 0.661 AC: 3811 AN: 5764

European-Non Finnish (NFE) AF: 0.713 AC: 792286 AN: 1111400

Other (OTH) AF: 0.705 AC: 42528 AN: 60364

GnomAD4 genome AF: 0.672 AC: 102199 AN: 151972 Hom.: 35116 Cov.: 31 AF XY: 0.678 AC XY: 50329 AN XY: 74278

African (AFR) AF: 0.530 AC: 21940 AN: 41392

American (AMR) AF: 0.758 AC: 11574 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.738 AC: 2563 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4469 AN: 5170

South Asian (SAS) AF: 0.660 AC: 3181 AN: 4822

European-Finnish (FIN) AF: 0.755 AC: 7963 AN: 10554

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48202 AN: 67968

Other (OTH) AF: 0.668 AC: 1413 AN: 2114

Alfa AF: 0.691 Hom.: 32303

Bravo AF: 0.670

Asia WGS AF: 0.764 AC: 2657 AN: 3478

EpiCase AF: 0.701

EpiControl AF: 0.703

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Werner syndrome (4)
-	-	2	not provided (2)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.3
DANN	Benign	0.43
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1800389; hg19: chr8-30924557; COSMIC: COSV108141453;