rs387907356

Variant names:

• chr12-48981411-C-A
• rs387907356
• NM_005430.4:c.884C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-48981411-C-A
• chr12-48981411-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_005430.4(WNT1):​c.884C>A​(p.Ser295*) variant causes a stop gained 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000577069: Functional studies demonstrate that the S295X variant impairs the WNT signaling pathway and results in decreased mineralization (Laine et al., 2013)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WNT1 NM_005430.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.14
• Publications: 10 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: Pathogenic. The variant received 18 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 11 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000577069: Functional studies demonstrate that the S295X variant impairs the WNT signaling pathway and results in decreased mineralization (Laine et al., 2013).; SCV003441255: Experimental studies have shown that this premature translational stop signal affects WNT1 function (PMID: 23656646).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-48981411-C-A is Pathogenic according to our data. Variant chr12-48981411-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.884C>A	p.Ser295*	stop_gained	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.884C>A	p.Ser295*	stop_gained	Exon 4 of 4	ENSP00000293549.3	P04628
	ENSG00000305774	ENST00000812875.1		n.146+460G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1427950 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 707290

African (AFR) AF: 0.00 AC: 0 AN: 32514

American (AMR) AF: 0.00 AC: 0 AN: 40354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25384

East Asian (EAS) AF: 0.00 AC: 0 AN: 37886

South Asian (SAS) AF: 0.00 AC: 0 AN: 82082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094618

Other (OTH) AF: 0.00 AC: 0 AN: 59030

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Osteogenesis imperfecta type 15 (1)
1	-	-	OSTEOPOROSIS, EARLY-ONSET, SUSCEPTIBILITY TO;C3808844:Osteogenesis imperfecta type 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.1
Vest4		0.88
GERP RS		4.2
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387907356; hg19: chr12-49375194;