17-46875155-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003396.3(WNT9B):c.389C>A(p.Thr130Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

WNT9B
NM_003396.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

WNT9B (HGNC:12779): (Wnt family member 9B) The WNT gene family consists of structurally related genes that 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. Study of its expression in the teratocarcinoma cell line NT2 suggests that it may be implicated in the early process of neuronal differentiation of NT2 cells induced by retinoic acid. This gene is clustered with WNT3, another family member, in the chromosome 17q21 region. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

WNT9B links:

LRRC37A2 (HGNC:):

LRRC37A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4033545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
WNT9B	NM_003396.3 linkuse as main transcript	c.389C>A	p.Thr130Asn	missense_variant	3/4	ENST00000290015.7
WNT9B	NM_001320458.2 linkuse as main transcript	c.389C>A	p.Thr130Asn	missense_variant	3/5
WNT9B	XM_011525178.3 linkuse as main transcript	c.407C>A	p.Thr136Asn	missense_variant	3/4
LRRC37A2	XM_024450773.2 linkuse as main transcript	c.4810-173901C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
WNT9B	ENST00000290015.7 linkuse as main transcript	c.389C>A	p.Thr130Asn	missense_variant	3/4	1	NM_003396.3	P1
WNT9B	ENST00000393461.2 linkuse as main transcript	c.389C>A	p.Thr130Asn	missense_variant	3/5	2
WNT9B	ENST00000575372.5 linkuse as main transcript			downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250450

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2021

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with WNT9B-related conditions. This variant is present in population databases (rs371468509, ExAC 0.02%). This sequence change replaces threonine with asparagine at codon 130 of the WNT9B protein (p.Thr130Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;.

Eigen

Benign

-0.071

Eigen_PC

Benign

0.051

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.085

MetaRNN

Benign

0.40

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.024

B;B

Vest4

0.47

MVP

0.77

MPC

0.36

ClinPred

0.18

GERP RS

4.6

Varity_R

0.31

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over