Variant chr12-48978652-TG-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_005430.4(WNT1):c.6del(p.Leu3_?2) variant causes a frameshift, start lost change. The variant allele was found at a frequency of 0.00000347 in 1,440,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

WNT1
NM_005430.4 frameshift, start_lost

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.88

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 36 pathogenic variants in the truncated region.

PS1

Another start lost variant in NM_005430.4 (WNT1) was described as [Pathogenic] in ClinVar as 2117080

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-48978652-TG-T is Pathogenic according to our data. Variant chr12-48978652-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2636643.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-48978652-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WNT1	NM_005430.4 linkuse as main transcript	c.6del	p.Leu3_?2	frameshift_variant, start_lost	1/4	ENST00000293549.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WNT1	ENST00000293549.4 linkuse as main transcript	c.6del	p.Leu3_?2	frameshift_variant, start_lost	1/4	1	NM_005430.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000138

AC:

AN:

216826

Hom.:

AF XY:

0.00000842

AC XY:

AN XY:

118778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000739

Gnomad NFE exome

AF:

0.0000103

Gnomad OTH exome

AF:

0.000183

GnomAD4 exome

AF:

0.00000347

AC:

AN:

1440996

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

716164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000223

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

WNT1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2023

The WNT1 c.6delG variant is predicted to result in a frameshift and premature protein termination (p.Leu3Serfs*36). This variant has been reported in the homozygous state in two siblings with autosomal recessive osteogenesis imperfecta (Kuptanon et al 2018. PubMed ID: 30012084). This variant is reported in 0.0074% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-49372435-TG-T). Frameshift variants in WNT1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over