12-48966316-A-T

Position:

• chr12-48966316-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_003394.4(WNT10B):​c.949T>A​(p.Phe317Ile) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WNT10B NM_003394.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 12-48966316-A-T is Pathogenic according to our data. Variant chr12-48966316-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 634648.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNT10B	NM_003394.4	c.949T>A	p.Phe317Ile	missense_variant	5/5	ENST00000301061.9	NP_003385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT10B	ENST00000301061.9	c.949T>A	p.Phe317Ile	missense_variant	5/5	1	NM_003394.4	ENSP00000301061.4
WNT10B	ENST00000407467.5	c.*231T>A		3_prime_UTR_variant	6/6	2		ENSP00000384691.1
WNT10B	ENST00000403957.5	c.*231T>A		3_prime_UTR_variant	6/6	5		ENSP00000385980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Split hand-foot malformation 6 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Sep 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.76		Gain of catalytic residue at E312 (P = 0.0372);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.95
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49360099;