17-46872653-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003396.3(WNT9B):c.214C>T(p.Pro72Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WNT9B NM_003396.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT9B	NM_003396.3	c.214C>T	p.Pro72Ser	missense_variant	2/4	ENST00000290015.7
WNT9B	NM_001320458.2	c.214C>T	p.Pro72Ser	missense_variant	2/5
WNT9B	XM_011525178.3	c.232C>T	p.Pro78Ser	missense_variant	2/4
LRRC37A2	XM_024450773.2	c.4810-176403C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT9B	ENST00000290015.7	c.214C>T	p.Pro72Ser	missense_variant	2/4	1	NM_003396.3	P1
WNT9B	ENST00000393461.2	c.214C>T	p.Pro72Ser	missense_variant	2/5	2
WNT9B	ENST00000575372.5	c.232C>T	p.Pro78Ser	missense_variant	2/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461284 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726960

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.214C>T (p.P72S) alteration is located in exon 2 (coding exon 2) of the WNT9B gene. This alteration results from a C to T substitution at nucleotide position 214, causing the proline (P) at amino acid position 72 to be replaced by a serine (S). 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	0.25
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Uncertain	0.029	D;D;T
Polyphen		0.86, 0.89	.;P;P
Vest4		0.77, 0.77
MutPred		0.65		.;Gain of phosphorylation at P72 (P = 0.0084);Gain of phosphorylation at P72 (P = 0.0084);
MVP		0.89
MPC		0.93
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.50
gMVP		0.75

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: rs1282713416; hg19: chr17-44950019;