Genetic Variant WRN:p.Gln1229Leu (chr8-31150454-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000553.6(WRN):c.3686A>T(p.Gln1229Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1229P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

WRN
NM_000553.6 missense, splice_region

Scores

Splicing: ADA: 0.9983

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.55

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 8-31150454-A-T is Pathogenic according to our data. Variant chr8-31150454-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5450.Status of the report is no_assertion_criteria_provided, 0 stars.

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.3686A>T	p.Gln1229Leu	missense splice_region	Exon 31 of 35	NP_000544.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WRN	ENST00000298139.7	TSL:1 MANE Select	c.3686A>T	p.Gln1229Leu	missense splice_region	Exon 31 of 35	ENSP00000298139.5
WRN	ENST00000521620.5	TSL:1	n.2319A>T		splice_region non_coding_transcript_exon	Exon 19 of 23
WRN	ENST00000650667.1		n.*3300A>T		splice_region non_coding_transcript_exon	Exon 30 of 34	ENSP00000498593.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Werner syndrome

Pathogenic:1

Nov 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

-0.071

Eigen_PC

Benign

0.062

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.60

M_CAP

Benign

0.015

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.5

PhyloP100

3.6

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.085

Sift

Benign

0.062

Sift4G

Benign

0.16

Polyphen

0.0010

Vest4

0.50

MutPred

0.42

Loss of catalytic residue at Q1229 (P = 0.0255)

MVP

0.62

MPC

0.067

ClinPred

0.97

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.52

Mutation Taster

=20/80

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.58

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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