rs1060500075

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000553.6(WRN):c.1606C>G(p.Gln536Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q536Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

WRN
NM_000553.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

Publications

3 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2910589).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WRN	NM_000553.6 link	c.1606C>G	p.Gln536Glu	missense_variant	Exon 13 of 35	ENST00000298139.7	NP_000544.2	Q14191

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WRN	ENST00000298139.7 link	c.1606C>G	p.Gln536Glu	missense_variant	Exon 13 of 35	1	NM_000553.6	ENSP00000298139.5	Q14191
WRN	ENST00000521620.5 link	n.307C>G		non_coding_transcript_exon_variant	Exon 2 of 23	1
WRN	ENST00000650667.1 link	n.*1220C>G		non_coding_transcript_exon_variant	Exon 12 of 34			ENSP00000498593.1	A0A494C0M3
WRN	ENST00000650667.1 link	n.*1220C>G		3_prime_UTR_variant	Exon 12 of 34			ENSP00000498593.1	A0A494C0M3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.00

AC:

AN:

85894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110794

Other (OTH)

AF:

0.00

AC:

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Werner syndrome

Uncertain:1

Aug 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with WRN-related disease. ClinVar contains an entry for this variant (Variation ID: 404042). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 536 of the WRN protein (p.Gln536Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.68

M_CAP

Benign

0.013

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PhyloP100

3.3

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

REVEL

Benign

0.086

Sift

Benign

0.045

Sift4G

Benign

0.096

Polyphen

0.78

Vest4

0.25

MutPred

0.41

Gain of disorder (P = 0.0927);

MVP

0.63

MPC

0.079

ClinPred

0.73

GERP RS

5.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.45

gMVP

0.66

Mutation Taster

=71/29

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over