NM_005430.4:c.859dupC
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_005430.4(WNT1):c.859dupC(p.His287ProfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic,risk factor (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Consequence
WNT1
NM_005430.4 frameshift
NM_005430.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.995
Publications
3 publications found
Genes affected
WNT1 (HGNC:12774): (Wnt family member 1) 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 is very conserved in evolution, and the protein encoded by this gene is known to be 98% identical to the mouse Wnt1 protein at the amino acid level. The studies in mouse indicate that the Wnt1 protein functions in the induction of the mesencephalon and cerebellum. This gene was originally considered as a candidate gene for Joubert syndrome, an autosomal recessive disorder with cerebellar hypoplasia as a leading feature. However, further studies suggested that the gene mutations might not have a significant role in Joubert syndrome. This gene is clustered with another family member, WNT10B, in the chromosome 12q13 region. [provided by RefSeq, Jul 2008]
WNT1 Gene-Disease associations (from GenCC):
- osteogenesis imperfecta type 15Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
- idiopathic juvenile osteoporosisInheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- osteogenesis imperfecta type 3Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- osteogenesis imperfecta type 4Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-48981380-T-TC is Pathogenic according to our data. Variant chr12-48981380-T-TC is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 50257.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005430.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| WNT1 | NM_005430.4 | MANE Select | c.859dupC | p.His287ProfsTer30 | frameshift | Exon 4 of 4 | NP_005421.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| WNT1 | ENST00000293549.4 | TSL:1 MANE Select | c.859dupC | p.His287ProfsTer30 | frameshift | Exon 4 of 4 | ENSP00000293549.3 | ||
| ENSG00000305774 | ENST00000812875.1 | n.146+490dupG | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 7.03e-7 AC: 1AN: 1422080Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 704022 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1422080
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
704022
show subpopulations
African (AFR)
AF:
AC:
0
AN:
31912
American (AMR)
AF:
AC:
0
AN:
39608
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25304
East Asian (EAS)
AF:
AC:
0
AN:
37196
South Asian (SAS)
AF:
AC:
0
AN:
81802
European-Finnish (FIN)
AF:
AC:
0
AN:
50028
Middle Eastern (MID)
AF:
AC:
0
AN:
5710
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1091788
Other (OTH)
AF:
AC:
0
AN:
58732
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
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0
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1
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2
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0.60
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic; risk factor
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 15 Pathogenic:1
Apr 04, 2013
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
OSTEOPOROSIS, EARLY-ONSET, SUSCEPTIBILITY TO Other:1
Apr 04, 2013
OMIM
Significance:risk factor
Review Status:no assertion criteria provided
Collection Method:literature only
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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