17-46872729-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BP4_Moderate BP6_Moderate

The NM_003396.3(WNT9B):c.290G>A(p.Arg97His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,612,600 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: WNT9B NM_003396.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.86

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.24017912).
• BP6: Variant 17-46872729-G-A is Benign according to our data. Variant chr17-46872729-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3046360.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT9B	NM_003396.3	c.290G>A	p.Arg97His	missense_variant	2/4	ENST00000290015.7
WNT9B	NM_001320458.2	c.290G>A	p.Arg97His	missense_variant	2/5
WNT9B	XM_011525178.3	c.308G>A	p.Arg103His	missense_variant	2/4
LRRC37A2	XM_024450773.2	c.4810-176327G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT9B	ENST00000290015.7	c.290G>A	p.Arg97His	missense_variant	2/4	1	NM_003396.3	P1
WNT9B	ENST00000393461.2	c.290G>A	p.Arg97His	missense_variant	2/5	2
WNT9B	ENST00000575372.5	c.308G>A	p.Arg103His	missense_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151998 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000297 AC: 73 AN: 245494 Hom.: 0 AF XY: 0.000389 AC XY: 52 AN XY: 133644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000162 AC: 236 AN: 1460484 Hom.: 1 Cov.: 32 AF XY: 0.000237 AC XY: 172 AN XY: 726492

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000844 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000297 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

WNT9B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.031	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92, 0.85
MVP		0.98
MPC		1.0
ClinPred		0.42	T
GERP RS		4.5
Varity_R		0.78
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201223229; hg19: chr17-44950095;