rs1800392

Variant names:

• chr8-31116441-G-T
• rs1800392
• NM_000553.6:c.2361G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-31116441-G-T
• chr8-31116441-G-C

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.2361G>T​(p.Leu787Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,613,630 control chromosomes in the GnomAD database, including 169,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L787L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (15419 hom., cov: 32)
  • Exomes 𝑓: 0.46 (154051 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.625
• Publications: 50 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=-0.74).
• BP6: Variant 8-31116441-G-T is Benign according to our data. Variant chr8-31116441-G-T is described in ClinVar as Benign. ClinVar VariationId is 130758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.625 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.585 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.2361G>T	p.Leu787Leu	synonymous	Exon 20 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.2361G>T	p.Leu787Leu	synonymous	Exon 20 of 35	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.994G>T		non_coding_transcript_exon	Exon 8 of 23
	WRN	ENST00000966176.1		c.2376G>T	p.Leu792Leu	synonymous	Exon 20 of 35	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67686 AN: 151856 Hom.: 15404 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.461

GnomAD2 exomes AF: 0.454 AC: 114045 AN: 251188 AF XY: 0.446

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.559

Gnomad ASJ exome AF: 0.452

Gnomad EAS exome AF: 0.629

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.456 AC: 666223 AN: 1461654 Hom.: 154051 Cov.: 51 AF XY: 0.451 AC XY: 327785 AN XY: 727126

African (AFR) AF: 0.414 AC: 13868 AN: 33474

American (AMR) AF: 0.555 AC: 24818 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11715 AN: 26132

East Asian (EAS) AF: 0.597 AC: 23660 AN: 39658

South Asian (SAS) AF: 0.333 AC: 28692 AN: 86250

European-Finnish (FIN) AF: 0.368 AC: 19641 AN: 53374

Middle Eastern (MID) AF: 0.374 AC: 2159 AN: 5766

European-Non Finnish (NFE) AF: 0.462 AC: 514163 AN: 1111900

Other (OTH) AF: 0.456 AC: 27507 AN: 60380

GnomAD4 genome AF: 0.446 AC: 67736 AN: 151976 Hom.: 15419 Cov.: 32 AF XY: 0.442 AC XY: 32825 AN XY: 74282

African (AFR) AF: 0.414 AC: 17142 AN: 41432

American (AMR) AF: 0.540 AC: 8255 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1584 AN: 3472

East Asian (EAS) AF: 0.603 AC: 3105 AN: 5148

South Asian (SAS) AF: 0.322 AC: 1550 AN: 4820

European-Finnish (FIN) AF: 0.362 AC: 3826 AN: 10564

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30898 AN: 67948

Other (OTH) AF: 0.462 AC: 974 AN: 2110

Alfa AF: 0.456 Hom.: 78839

Bravo AF: 0.463

Asia WGS AF: 0.464 AC: 1611 AN: 3476

EpiCase AF: 0.446

EpiControl AF: 0.451

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	-0.74
CADD	Benign	7.4
DANN	Benign	0.61
PhyloP100		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1800392; hg19: chr8-30973957; COSMIC: COSV53300277; COSMIC: COSV53300277;