8-31167122-C-T

Variant names:

• chr8-31167122-C-T
• rs1801196
• NM_000553.6:c.4083C>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.4083C>T​(p.Ser1361Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,612,856 control chromosomes in the GnomAD database, including 70,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6487 hom., cov: 32)
  • Exomes 𝑓: 0.30 (64491 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.725
• Publications: 25 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• osteosarcoma

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

ENSG00000253961 (HGNC:58431):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 8-31167122-C-T is Benign according to our data. Variant chr8-31167122-C-T is described in ClinVar as Benign. ClinVar VariationId is 130761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.725 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.325 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.4083C>T	p.Ser1361Ser	synonymous	Exon 34 of 35	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.4083C>T	p.Ser1361Ser	synonymous	Exon 34 of 35	ENSP00000298139.5
	WRN	ENST00000521620.5	TSL:1	n.2716C>T		non_coding_transcript_exon	Exon 22 of 23
	ENSG00000253961	ENST00000521252.1	TSL:5	n.252G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43870 AN: 151732 Hom.: 6484 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.297 AC: 74521 AN: 250948 AF XY: 0.301

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.296 AC: 432983 AN: 1461004 Hom.: 64491 Cov.: 36 AF XY: 0.298 AC XY: 216576 AN XY: 726802

African (AFR) AF: 0.261 AC: 8742 AN: 33448

American (AMR) AF: 0.263 AC: 11749 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 8203 AN: 26118

East Asian (EAS) AF: 0.282 AC: 11177 AN: 39662

South Asian (SAS) AF: 0.340 AC: 29287 AN: 86210

European-Finnish (FIN) AF: 0.349 AC: 18649 AN: 53388

Middle Eastern (MID) AF: 0.353 AC: 2034 AN: 5764

European-Non Finnish (NFE) AF: 0.293 AC: 325128 AN: 1111430

Other (OTH) AF: 0.298 AC: 18014 AN: 60350

GnomAD4 genome AF: 0.289 AC: 43877 AN: 151852 Hom.: 6487 Cov.: 32 AF XY: 0.292 AC XY: 21670 AN XY: 74222

African (AFR) AF: 0.268 AC: 11110 AN: 41420

American (AMR) AF: 0.267 AC: 4068 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1070 AN: 3466

East Asian (EAS) AF: 0.244 AC: 1261 AN: 5158

South Asian (SAS) AF: 0.338 AC: 1632 AN: 4822

European-Finnish (FIN) AF: 0.348 AC: 3668 AN: 10540

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 19952 AN: 67906

Other (OTH) AF: 0.293 AC: 618 AN: 2106

Alfa AF: 0.291 Hom.: 11394

Bravo AF: 0.280

Asia WGS AF: 0.292 AC: 1016 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.307

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.54
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801196; hg19: chr8-31024638; COSMIC: COSV53295659; COSMIC: COSV53295659;