12-48966364-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003394.4(WNT10B):c.901C>T(p.Pro301Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0193 in 1,614,224 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.012 (31 hom., cov: 32)
  • Exomes 𝑓: 0.020 (371 hom.)
• Consequence: WNT10B NM_003394.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.38

Genes affected

WNT10B (HGNC:12775): (Wnt family member 10B) The WNT gene family consists of structurally related genes which 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. It may be involved in breast cancer, and its protein signaling is likely a molecular switch that governs adipogenesis. This protein is 96% identical to the mouse Wnt10b protein at the amino acid level. This gene is clustered with another family member, WNT1, in the chromosome 12q13 region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006138742).
• BP6: Variant 12-48966364-G-A is Benign according to our data. Variant chr12-48966364-G-A is described in ClinVar as [Benign]. Clinvar id is 782957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48966364-G-A is described in Lovd as [Benign]. Variant chr12-48966364-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1850/152344) while in subpopulation NFE AF= 0.0194 (1322/68038). AF 95% confidence interval is 0.0186. There are 31 homozygotes in gnomad4. There are 869 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT10B	NM_003394.4	c.901C>T	p.Pro301Ser	missense_variant	5/5	ENST00000301061.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10B	ENST00000301061.9	c.901C>T	p.Pro301Ser	missense_variant	5/5	1	NM_003394.4	P1
WNT10B	ENST00000403957.5	c.*183C>T		3_prime_UTR_variant	6/6	5
WNT10B	ENST00000407467.5	c.*183C>T		3_prime_UTR_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1850 AN: 152226 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0106 AC: 2655 AN: 250728 Hom.: 29 AF XY: 0.0105 AC XY: 1423 AN XY: 135708

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.00622

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0201 AC: 29319 AN: 1461880 Hom.: 371 Cov.: 34 AF XY: 0.0192 AC XY: 13950 AN XY: 727242

Gnomad4 AFR exome AF: 0.00296

Gnomad4 AMR exome AF: 0.00657

Gnomad4 ASJ exome AF: 0.00432

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0121 AC: 1850 AN: 152344 Hom.: 31 Cov.: 32 AF XY: 0.0117 AC XY: 869 AN XY: 74484

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.0157 Hom.: 43

Bravo AF: 0.0111

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.00968 AC: 1175

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0172

EpiControl AF: 0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2020	This variant is associated with the following publications: (PMID: 20579865, 16477437, 23104151) -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

WNT10B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.73	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.24
Sift	Benign	0.66	T
Sift4G	Benign	0.33	T
Polyphen		0.027	B
Vest4		0.16
MPC		0.73
ClinPred		0.017	T
GERP RS		4.4
Varity_R		0.075
gMVP		0.42

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: rs35034312; hg19: chr12-49360147; COSMIC: COSV99975719; COSMIC: COSV99975719;