17-46872759-G-T

Variant names:

• chr17-46872759-G-T
• rs1329606333
• NM_003396.3:c.320G>T

Variant summary

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

The NM_003396.3(WNT9B):​c.320G>T​(p.Gly107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,122 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WNT9B NM_003396.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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]

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]

ACMG classification

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	c.320G>T	p.Gly107Val	missense_variant	Exon 2 of 4	ENST00000290015.7	NP_003387.1
WNT9B	NM_001320458.2	c.320G>T	p.Gly107Val	missense_variant	Exon 2 of 5		NP_001307387.1
WNT9B	XM_011525178.3	c.338G>T	p.Gly113Val	missense_variant	Exon 2 of 4		XP_011523480.1
LRRC37A2	XM_024450773.2	c.4810-176297G>T		intron_variant	Intron 10 of 10		XP_024306541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT9B	ENST00000290015.7	c.320G>T	p.Gly107Val	missense_variant	Exon 2 of 4	1	NM_003396.3	ENSP00000290015.2
WNT9B	ENST00000393461.2	c.320G>T	p.Gly107Val	missense_variant	Exon 2 of 5	2		ENSP00000377105.2
WNT9B	ENST00000575372.5	c.338G>T	p.Gly113Val	missense_variant	Exon 2 of 3	4		ENSP00000458192.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454122 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 723136

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.320G>T (p.G107V) alteration is located in exon 2 (coding exon 2) of the WNT9B gene. This alteration results from a G to T substitution at nucleotide position 320, causing the glycine (G) at amino acid position 107 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Uncertain	0.46	.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	.;N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.23
Sift	Benign	0.14	.;T;T
Sift4G	Uncertain	0.060	T;T;T
Polyphen		0.025, 0.68	.;B;P
Vest4		0.43, 0.44
MutPred		0.48		.;Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.83
MPC		0.48
ClinPred		0.35	T
GERP RS		2.3
Varity_R		0.15
gMVP		0.38

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

Other links and lift over

dbSNP: rs1329606333; hg19: chr17-44950125;