12-48981380-TC-TCC

Variant names:

• chr12-48981380-T-TC
• rs387907353
• NM_005430.4:c.859dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

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
• Clinical Significance: Pathogenic; risk factor no assertion criteria provided P:1 O:1
• 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 15

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

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

Sel.	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	P04628

Ensembl Transcripts

Sel.	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	P04628
	ENSG00000305774	ENST00000812875.1		n.146+490dupG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 704022

African (AFR) AF: 0.00 AC: 0 AN: 31912

American (AMR) AF: 0.00 AC: 0 AN: 39608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 37196

South Asian (SAS) AF: 0.00 AC: 0 AN: 81802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091788

Other (OTH) AF: 0.00 AC: 0 AN: 58732

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Osteogenesis imperfecta type 15 (1)
-	-	-	OSTEOPOROSIS, EARLY-ONSET, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99
Mutation Taster		=6/194	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: rs387907353; hg19: chr12-49375163;