Genetic Variant NM_003396.3:c.4C>A (chr17-46851642-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003396.3(WNT9B):c.4C>A(p.Arg2Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WNT9B
NM_003396.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92

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:32404): (leucine rich repeat containing 37 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC37A2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
WNT9B	NM_003396.3 link	c.4C>A	p.Arg2Ser	missense_variant	Exon 1 of 4	ENST00000290015.7	NP_003387.1	O14905
WNT9B	NM_001320458.2 link	c.4C>A	p.Arg2Ser	missense_variant	Exon 1 of 5		NP_001307387.1	E7EPC3
LRRC37A2	XM_024450773.2 link	c.4810-197414C>A		intron_variant	Intron 10 of 10		XP_024306541.1
WNT9B	XM_011525178.3 link	c.95+18202C>A		intron_variant	Intron 1 of 3		XP_011523480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
WNT9B	ENST00000290015.7 link	c.4C>A	p.Arg2Ser	missense_variant	Exon 1 of 4	1	NM_003396.3	ENSP00000290015.2	O14905
WNT9B	ENST00000393461.2 link	c.4C>A	p.Arg2Ser	missense_variant	Exon 1 of 5	2		ENSP00000377105.2	E7EPC3
WNT9B	ENST00000575372.5 link	c.95+18202C>A		intron_variant	Intron 1 of 2	4		ENSP00000458192.1	I3L0L8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1123050

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

541892

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 2 of the WNT9B protein (p.Arg2Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with WNT9B-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.69

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.20

N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.090

N;N

REVEL

Benign

0.28

Sift

Benign

0.57

T;D

Sift4G

Benign

0.72

T;T

Polyphen

0.013

B;B

Vest4

0.33

MutPred

0.28

Gain of glycosylation at R2 (P = 0.0024);Gain of glycosylation at R2 (P = 0.0024);

MVP

0.84

MPC

0.29

ClinPred

0.71

GERP RS

3.8

Varity_R

0.22

gMVP

0.33

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over