rs145080962

Positions:

• chr8-31088873-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000553.6(WRN):​c.1577-17T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,601,474 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.75

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 -16 ACMG points.

• BP6: Variant 8-31088873-T-G is Benign according to our data. Variant chr8-31088873-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 256706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00337 (513/152204) while in subpopulation AFR AF= 0.0117 (488/41562). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WRN	NM_000553.6	c.1577-17T>G		intron_variant		ENST00000298139.7	NP_000544.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WRN	ENST00000298139.7	c.1577-17T>G		intron_variant		1	NM_000553.6	ENSP00000298139.5
WRN	ENST00000521620.5	n.278-17T>G		intron_variant		1
WRN	ENST00000650667.1	n.*1191-17T>G		intron_variant				ENSP00000498593.1

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000988 AC: 235 AN: 237868 Hom.: 1 AF XY: 0.000679 AC XY: 87 AN XY: 128090

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000922

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.000681

GnomAD4 exome AF: 0.000373 AC: 540 AN: 1449270 Hom.: 3 Cov.: 30 AF XY: 0.000314 AC XY: 226 AN XY: 720056

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000299

Gnomad4 OTH exome AF: 0.000987

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00335 AC XY: 249 AN XY: 74412

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00381

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Werner syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2019

- -

Wiskott-Aldrich syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.51		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145080962; hg19: chr8-30946389;