1-22120162-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_030761.5(WNT4):​c.944T>G​(p.Phe315Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

WNT4
NM_030761.5 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 4.86
Variant links:
Genes affected
WNT4 (HGNC:12783): (Wnt family member 4) 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, and is the first signaling molecule shown to influence the sex-determination cascade. It encodes a protein which shows 98% amino acid identity to the Wnt4 protein of mouse and rat. This gene and a nuclear receptor known to antagonize the testis-determining factor play a concerted role in both the control of female development and the prevention of testes formation. This gene and another two family members, WNT2 and WNT7B, may be associated with abnormal proliferation in breast tissue. Mutations in this gene can result in Rokitansky-Kuster-Hauser syndrome and in SERKAL syndrome. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WNT4NM_030761.5 linkuse as main transcriptc.944T>G p.Phe315Cys missense_variant 5/5 ENST00000290167.11 NP_110388.2
WNT4XM_011541597.3 linkuse as main transcriptc.1010T>G p.Phe337Cys missense_variant 5/5 XP_011539899.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WNT4ENST00000290167.11 linkuse as main transcriptc.944T>G p.Phe315Cys missense_variant 5/51 NM_030761.5 ENSP00000290167 P1P56705-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Mullerian aplasia and hyperandrogenism Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
Mayer-Rokitansky-Kuster-Hauser syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
SERKAL syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.48
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.6
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.89
Gain of methylation at R313 (P = 0.118);
MVP
0.97
MPC
2.2
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.87
gMVP
0.98

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1334778982; hg19: chr1-22446655; API