8-31166927-C-T

Variant names:

• chr8-31166927-C-T
• rs4987036
• NM_000553.6:c.3983-95C>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.3983-95C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,253,908 control chromosomes in the GnomAD database, including 52,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6065 hom., cov: 32)
  • Exomes 𝑓: 0.29 (46859 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.282
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-31166927-C-T is Benign according to our data. Variant chr8-31166927-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.324 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.3983-95C>T		intron	N/A	NP_000544.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.3983-95C>T		intron	N/A	ENSP00000298139.5
	WRN	ENST00000521620.5	TSL:1	n.2616-95C>T		intron	N/A
	WRN	ENST00000966176.1		c.3998-95C>T		intron	N/A	ENSP00000636235.1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42152 AN: 151842 Hom.: 6062 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.289 AC: 318143 AN: 1101948 Hom.: 46859 AF XY: 0.291 AC XY: 160441 AN XY: 552096

African (AFR) AF: 0.213 AC: 5265 AN: 24704

American (AMR) AF: 0.250 AC: 7255 AN: 29012

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 6386 AN: 20710

East Asian (EAS) AF: 0.286 AC: 9829 AN: 34338

South Asian (SAS) AF: 0.332 AC: 21349 AN: 64364

European-Finnish (FIN) AF: 0.347 AC: 16016 AN: 46164

Middle Eastern (MID) AF: 0.340 AC: 1337 AN: 3930

European-Non Finnish (NFE) AF: 0.285 AC: 237008 AN: 831304

Other (OTH) AF: 0.289 AC: 13698 AN: 47422

GnomAD4 genome AF: 0.277 AC: 42160 AN: 151960 Hom.: 6065 Cov.: 32 AF XY: 0.281 AC XY: 20877 AN XY: 74248

African (AFR) AF: 0.228 AC: 9461 AN: 41476

American (AMR) AF: 0.263 AC: 4014 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1071 AN: 3468

East Asian (EAS) AF: 0.244 AC: 1260 AN: 5174

South Asian (SAS) AF: 0.338 AC: 1627 AN: 4812

European-Finnish (FIN) AF: 0.349 AC: 3678 AN: 10540

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

European-Non Finnish (NFE) AF: 0.294 AC: 19948 AN: 67922

Other (OTH) AF: 0.285 AC: 602 AN: 2112

Alfa AF: 0.285 Hom.: 1051

Bravo AF: 0.267

Asia WGS AF: 0.290 AC: 1010 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.7
DANN	Benign	0.63
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4987036; hg19: chr8-31024443;