8-31169798-T-C

Variant names:

• chr8-31169798-T-C
• rs2553256
• NM_000553.6:c.4191+2568T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000553.6(WRN):​c.4191+2568T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 151,826 control chromosomes in the GnomAD database, including 10,959 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (10959 hom., cov: 31)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 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.4191+2568T>C		intron	N/A	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.4191+2568T>C		intron	N/A	ENSP00000298139.5
	WRN	ENST00000521620.5	TSL:1	n.2824+2568T>C		intron	N/A
	ENSG00000253961	ENST00000521252.1	TSL:5	n.182-2606A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56707 AN: 151710 Hom.: 10953 Cov.: 31

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.374 AC: 56742 AN: 151826 Hom.: 10959 Cov.: 31 AF XY: 0.372 AC XY: 27591 AN XY: 74228

African (AFR) AF: 0.332 AC: 13748 AN: 41392

American (AMR) AF: 0.476 AC: 7247 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1504 AN: 3468

East Asian (EAS) AF: 0.580 AC: 2987 AN: 5148

South Asian (SAS) AF: 0.284 AC: 1365 AN: 4810

European-Finnish (FIN) AF: 0.286 AC: 3014 AN: 10528

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25681 AN: 67930

Other (OTH) AF: 0.393 AC: 829 AN: 2112

Alfa AF: 0.369 Hom.: 5576

Bravo AF: 0.394

Asia WGS AF: 0.441 AC: 1531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.76
PhyloP100		-0.025
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: rs2553256; hg19: chr8-31027314;