rs727505392

Variant names:

• chr12-48981551-AC-A
• rs727505392
• NM_005430.4:c.1026delC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_005430.4(WNT1):​c.1026delC​(p.Glu343SerfsTer50) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,384 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: WNT1 NM_005430.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.11
• Publications: 1 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 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• idiopathic juvenile osteoporosis

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305774 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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. Fraction of 0.0782 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-48981551-AC-A is Pathogenic according to our data. Variant chr12-48981551-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 180210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT1	NM_005430.4	c.1026delC	p.Glu343SerfsTer50	frameshift_variant	Exon 4 of 4	ENST00000293549.4	NP_005421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT1	ENST00000293549.4	c.1026delC	p.Glu343SerfsTer50	frameshift_variant	Exon 4 of 4	1	NM_005430.4	ENSP00000293549.3
ENSG00000305774	ENST00000812875.1	n.146+319delG		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383384 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681820

African (AFR) AF: 0.00 AC: 0 AN: 30606

American (AMR) AF: 0.00 AC: 0 AN: 34578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24464

East Asian (EAS) AF: 0.00 AC: 0 AN: 35076

South Asian (SAS) AF: 0.00 AC: 0 AN: 77954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074102

Other (OTH) AF: 0.00 AC: 0 AN: 57396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 15 Pathogenic:1

Nov 17, 2014

Mendelics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:1

Mar 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu343Serfs*50) in the WNT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the WNT1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with early-onset osteoporosis and bone fractures (PMID: 28116328). ClinVar contains an entry for this variant (Variation ID: 180210). This variant disrupts a region of the WNT1 protein in which other variant(s) (p.Val355Phe) have been determined to be pathogenic (PMID: 23434763, 25010833). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727505392; hg19: chr12-49375334;