8-31141606-C-T

Variant names:

• chr8-31141606-C-T
• rs3024239
• NM_000553.6:c.3138+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000553.6(WRN):​c.3138+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,613,698 control chromosomes in the GnomAD database, including 186,689 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14117 hom., cov: 30)
  • Exomes 𝑓: 0.48 (172572 hom.)
• Consequence: WRN NM_000553.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008950
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0870
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-31141606-C-T is Benign according to our data. Variant chr8-31141606-C-T is described in ClinVar as Benign. ClinVar VariationId is 130754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.577 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.3138+6C>T		splice_region 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.3138+6C>T		splice_region intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000521620.5	TSL:1	n.1771+6C>T		splice_region intron	N/A
	WRN	ENST00000966176.1		c.3153+6C>T		splice_region intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61669 AN: 151764 Hom.: 14117 Cov.: 30

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.423

GnomAD2 exomes AF: 0.470 AC: 118232 AN: 251362 AF XY: 0.483

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.481 AC: 703811 AN: 1461818 Hom.: 172572 Cov.: 59 AF XY: 0.487 AC XY: 353843 AN XY: 727212

African (AFR) AF: 0.184 AC: 6163 AN: 33480

American (AMR) AF: 0.404 AC: 18063 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 13307 AN: 26132

East Asian (EAS) AF: 0.371 AC: 14730 AN: 39692

South Asian (SAS) AF: 0.585 AC: 50479 AN: 86258

European-Finnish (FIN) AF: 0.569 AC: 30405 AN: 53418

Middle Eastern (MID) AF: 0.558 AC: 3219 AN: 5768

European-Non Finnish (NFE) AF: 0.485 AC: 538885 AN: 1111958

Other (OTH) AF: 0.473 AC: 28560 AN: 60394

GnomAD4 genome AF: 0.406 AC: 61670 AN: 151880 Hom.: 14117 Cov.: 30 AF XY: 0.412 AC XY: 30594 AN XY: 74224

African (AFR) AF: 0.198 AC: 8206 AN: 41440

American (AMR) AF: 0.392 AC: 5989 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1729 AN: 3466

East Asian (EAS) AF: 0.357 AC: 1837 AN: 5142

South Asian (SAS) AF: 0.595 AC: 2851 AN: 4790

European-Finnish (FIN) AF: 0.572 AC: 6032 AN: 10546

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33440 AN: 67918

Other (OTH) AF: 0.423 AC: 892 AN: 2108

Alfa AF: 0.466 Hom.: 16036

Bravo AF: 0.379

Asia WGS AF: 0.452 AC: 1572 AN: 3478

EpiCase AF: 0.504

EpiControl AF: 0.502

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.25
PhyloP100		-0.087
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000090
dbscSNV1_RF	Benign	0.0040
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: rs3024239; hg19: chr8-30999122; COSMIC: COSV53296199;