12-48966411-A-G

Position:

• chr12-48966411-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_003394.4(WNT10B):​c.854T>C​(p.Ile285Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000615 in 1,614,030 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00053 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: WNT10B NM_003394.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.12

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30538112).
• BP6: Variant 12-48966411-A-G is Benign according to our data. Variant chr12-48966411-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2069153.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000532 (81/152310) while in subpopulation SAS AF= 0.00186 (9/4830). AF 95% confidence interval is 0.000971. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT10B	NM_003394.4	c.854T>C	p.Ile285Thr	missense_variant	5/5	ENST00000301061.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT10B	ENST00000301061.9	c.854T>C	p.Ile285Thr	missense_variant	5/5	1	NM_003394.4	P1
WNT10B	ENST00000403957.5	c.*136T>C		3_prime_UTR_variant	6/6	5
WNT10B	ENST00000407467.5	c.*136T>C		3_prime_UTR_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000631 AC: 158 AN: 250436 Hom.: 0 AF XY: 0.000796 AC XY: 108 AN XY: 135636

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000894

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000623 AC: 911 AN: 1461720 Hom.: 1 Cov.: 33 AF XY: 0.000692 AC XY: 503 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000665

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74482

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.000506

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.87	P
Vest4		0.67
MVP		0.94
MPC		1.1
ClinPred		0.087	T
GERP RS		4.4
Varity_R		0.58
gMVP		0.60

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: rs146010731; hg19: chr12-49360194; COSMIC: COSV56406464; COSMIC: COSV56406464;