Genetic Variant WNT1:p.Glu189Gln (chr12-48980630-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005430.4(WNT1):c.565G>C(p.Glu189Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,626 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

WNT1
NM_005430.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.87

Publications

0 publications found

Variant links:

Genes affected

WNT1 (HGNC:12774): (Wnt family member 1) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family. It is very conserved in evolution, and the protein encoded by this gene is known to be 98% identical to the mouse Wnt1 protein at the amino acid level. The studies in mouse indicate that the Wnt1 protein functions in the induction of the mesencephalon and cerebellum. This gene was originally considered as a candidate gene for Joubert syndrome, an autosomal recessive disorder with cerebellar hypoplasia as a leading feature. However, further studies suggested that the gene mutations might not have a significant role in Joubert syndrome. This gene is clustered with another family member, WNT10B, in the chromosome 12q13 region. [provided by RefSeq, Jul 2008]

WNT1 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 15
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
idiopathic juvenile osteoporosis
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

WNT1 links:

ENSG00000305774 (HGNC:):

ENSG00000305774 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT1	NM_005430.4 link	c.565G>C	p.Glu189Gln	missense_variant	Exon 3 of 4	ENST00000293549.4	NP_005421.1	P04628

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT1	ENST00000293549.4 link	c.565G>C	p.Glu189Gln	missense_variant	Exon 3 of 4	1	NM_005430.4	ENSP00000293549.3		P04628
ENSG00000305774	ENST00000812875.1 link	n.146+1241C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446626

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718462

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32986

American (AMR)

AF:

0.00

AC:

AN:

42306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25244

East Asian (EAS)

AF:

0.00

AC:

AN:

39400

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104358

Other (OTH)

AF:

0.00

AC:

AN:

59662

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.082

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.6

.;M

PhyloP100

6.9

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.1

.;N

REVEL

Uncertain

0.64

Sift

Uncertain

0.0030

.;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

.;D

Vest4

0.60

MutPred

0.69

Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);

MVP

0.92

ClinPred

0.99

GERP RS

4.9

Varity_R

0.78

gMVP

0.75

Mutation Taster

=39/61

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over