Genetic Variant WRN:c.840-2027G>T (chr8-31078840-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000553.6(WRN):c.840-2027G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 152,064 control chromosomes in the GnomAD database, including 34,783 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 0.67 ( 34783 hom., cov: 32)

Consequence

WRN
NM_000553.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0640

Publications

14 publications found

Variant links:

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

WRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.840-2027G>T		intron_variant	Intron 8 of 34	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.840-2027G>T	intron_variant	Intron 8 of 34	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000651642.1 link	c.135-2027G>T	intron_variant	Intron 2 of 3			ENSP00000498779.1	A0A494C0Y6
WRN	ENST00000650667.1 link	n.*454-2027G>T	intron_variant	Intron 7 of 33			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

AF:

0.670

AC:

101830

AN:

151946

Hom.:

34761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.540

Gnomad AMI

AF:

0.758

Gnomad AMR

AF:

0.757

Gnomad ASJ

AF:

0.731

Gnomad EAS

AF:

0.862

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.742

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.701

Gnomad OTH

AF:

0.660

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

GnomAD4 genome

AF:

0.670

AC:

101902

AN:

152064

Hom.:

34783

Cov.:

AF XY:

0.675

AC XY:

50200

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.540

AC:

22387

AN:

41464

American (AMR)

AF:

0.757

AC:

11568

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.731

AC:

2535

AN:

3468

East Asian (EAS)

AF:

0.862

AC:

4452

AN:

5162

South Asian (SAS)

AF:

0.659

AC:

3178

AN:

4826

European-Finnish (FIN)

AF:

0.742

AC:

7841

AN:

10570

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.701

AC:

47648

AN:

67986

Other (OTH)

AF:

0.663

AC:

1397

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1689

3378

5067

6756

8445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.692

Hom.:

51472

Bravo

AF:

0.669

Asia WGS

AF:

0.755

AC:

2624

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

8.1

(source)

DANN

Benign

0.70

PhyloP100

0.064

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over