12-48966368-CAGACGGGGCTGGA-C

Variant names:

• chr12-48966368-CAGACGGGGCTGGA-C
• rs758375129
• NM_003394.4:c.884_896delTCCAGCCCCGTCT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_003394.4(WNT10B):​c.884_896delTCCAGCCCCGTCT​(p.Phe295CysfsTer87) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: WNT10B NM_003394.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.18

Genes affected

WNT10B (HGNC:12775): (Wnt family member 10B) 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 may be involved in breast cancer, and its protein signaling is likely a molecular switch that governs adipogenesis. This protein is 96% identical to the mouse Wnt10b protein at the amino acid level. This gene is clustered with another family member, WNT1, in the chromosome 12q13 region. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-48966368-CAGACGGGGCTGGA-C is Pathogenic according to our data. Variant chr12-48966368-CAGACGGGGCTGGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 2098787.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT10B	NM_003394.4	c.884_896delTCCAGCCCCGTCT	p.Phe295CysfsTer87	frameshift_variant	Exon 5 of 5	ENST00000301061.9	NP_003385.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT10B	ENST00000301061.9	c.884_896delTCCAGCCCCGTCT	p.Phe295CysfsTer87	frameshift_variant	Exon 5 of 5	1	NM_003394.4	ENSP00000301061.4
WNT10B	ENST00000407467	c.*166_*178delTCCAGCCCCGTCT		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000384691.1
WNT10B	ENST00000403957	c.*166_*178delTCCAGCCCCGTCT		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000385980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 22, 2022

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.Phe295Cysfs*87) in the WNT10B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the WNT10B protein. This variant is present in population databases (rs758375129, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with split-hand/foot malformation (PMID: 32762550; Invitae). It has also been observed to segregate with disease in related individuals. This variant disrupts the C-terminus of the WNT10B protein. Other variant(s) that disrupt this region (p.Cys366*) have been observed in individuals with WNT10B-related conditions (PMID: 31998667). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs758375129; hg19: chr12-49360151;