8-31169798-T-C

Position:

• chr8-31169798-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.4191+2568T>C		intron_variant		ENST00000298139.7	NP_000544.2
WRN	XM_011544639.4	c.4110+2568T>C		intron_variant			XP_011542941.1
WRN	XM_011544640.2	c.2592+2568T>C		intron_variant			XP_011542942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.4191+2568T>C		intron_variant		1	NM_000553.6	ENSP00000298139.5

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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.378

Gnomad4 OTH AF: 0.393

Alfa AF: 0.368 Hom.: 4933

Bravo AF: 0.394

Asia WGS AF: 0.441 AC: 1531 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.7
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs2553256; hg19: chr8-31027314;