17-46872756-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003396.3(WNT9B):c.317T>C(p.Met106Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,590,790 control chromosomes in the GnomAD database, including 434,800 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.78 (45843 hom., cov: 26)
  • Exomes 𝑓: 0.74 (388957 hom.)
• Consequence: WNT9B NM_003396.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.834

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5856167E-7).
• BP6: Variant 17-46872756-T-C is Benign according to our data. Variant chr17-46872756-T-C is described in ClinVar as [Benign]. Clinvar id is 1598959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT9B	NM_003396.3	c.317T>C	p.Met106Thr	missense_variant	2/4	ENST00000290015.7
WNT9B	NM_001320458.2	c.317T>C	p.Met106Thr	missense_variant	2/5
WNT9B	XM_011525178.3	c.335T>C	p.Met112Thr	missense_variant	2/4
LRRC37A2	XM_024450773.2	c.4810-176300T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT9B	ENST00000290015.7	c.317T>C	p.Met106Thr	missense_variant	2/4	1	NM_003396.3	P1
WNT9B	ENST00000393461.2	c.317T>C	p.Met106Thr	missense_variant	2/5	2
WNT9B	ENST00000575372.5	c.335T>C	p.Met112Thr	missense_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.779 AC: 116673 AN: 149756 Hom.: 45800 Cov.: 26

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.787

Gnomad MID AF: 0.831

Gnomad NFE AF: 0.747

Gnomad OTH AF: 0.787

GnomAD3 exomes AF: 0.705 AC: 168856 AN: 239642 Hom.: 60833 AF XY: 0.708 AC XY: 92586 AN XY: 130756

Gnomad AFR exome AF: 0.907

Gnomad AMR exome AF: 0.614

Gnomad ASJ exome AF: 0.652

Gnomad EAS exome AF: 0.442

Gnomad SAS exome AF: 0.690

Gnomad FIN exome AF: 0.767

Gnomad NFE exome AF: 0.743

Gnomad OTH exome AF: 0.721

GnomAD4 exome AF: 0.736 AC: 1060645 AN: 1440920 Hom.: 388957 Cov.: 57 AF XY: 0.735 AC XY: 526634 AN XY: 716286

Gnomad4 AFR exome AF: 0.911

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.673

Gnomad4 EAS exome AF: 0.538

Gnomad4 SAS exome AF: 0.694

Gnomad4 FIN exome AF: 0.776

Gnomad4 NFE exome AF: 0.744

Gnomad4 OTH exome AF: 0.729

GnomAD4 genome AF: 0.779 AC: 116766 AN: 149870 Hom.: 45843 Cov.: 26 AF XY: 0.778 AC XY: 56893 AN XY: 73086

Gnomad4 AFR AF: 0.906

Gnomad4 AMR AF: 0.712

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.488

Gnomad4 SAS AF: 0.702

Gnomad4 FIN AF: 0.787

Gnomad4 NFE AF: 0.747

Gnomad4 OTH AF: 0.784

Alfa AF: 0.735 Hom.: 38719

Bravo AF: 0.769

TwinsUK AF: 0.737 AC: 2732

ALSPAC AF: 0.737 AC: 2842

ESP6500AA AF: 0.905 AC: 3968

ESP6500EA AF: 0.733 AC: 6275

ExAC AF: 0.710 AC: 85898

Asia WGS AF: 0.585 AC: 2036 AN: 3478

EpiCase AF: 0.743

EpiControl AF: 0.743

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

WNT9B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	2.4
Dann	Benign	0.33
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0083	N
MetaRNN	Benign	7.6e-7	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.48	T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.034, 0.023
MPC		0.30
ClinPred		0.0084	T
GERP RS		-0.034
Varity_R		0.071
gMVP		0.26

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: rs4968281; hg19: chr17-44950122; COSMIC: COSV51518533;