chr8-28555799-G-GA

Position:

• chr8-28555799-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_017412.4(FZD3):​c.1616dup​(p.Asp539GlufsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FZD3 NM_017412.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.92

Genes affected

FZD3 (HGNC:4041): (frizzled class receptor 3) This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. The function of this protein is unknown, although it may play a role in mammalian hair follicle development. Alternative splicing results in multiple transcript variants. This gene is a susceptibility locus for schizophrenia. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-28555799-G-GA is Pathogenic according to our data. Variant chr8-28555799-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632606.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FZD3	NM_017412.4	c.1616dup	p.Asp539GlufsTer32	frameshift_variant	7/8	ENST00000240093.8	NP_059108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FZD3	ENST00000240093.8	c.1616dup	p.Asp539GlufsTer32	frameshift_variant	7/8	1	NM_017412.4	ENSP00000240093	P1
FZD3	ENST00000537916.2	c.1616dup	p.Asp539GlufsTer32	frameshift_variant	6/7	2		ENSP00000437489	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Congenital cerebellar hypoplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Hydrocephalus;C0175754:Corpus callosum, agenesis of;C3714581:Multicystic kidney dysplasia;C5779613:Arthrogryposis multiplex congenita Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Dobyns Lab, Seattle Children's Research Institute

Feb 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1563406024; hg19: chr8-28413316;