rs80358301

Variant names:

• chr11-86951271-AATCCAC-A
• rs80358301
• NM_012193.4:c.1479_1484delGTGGAT

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_012193.4(FZD4):​c.1479_1484delGTGGAT​(p.Met493_Trp494del) variant causes a disruptive inframe deletion 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FZD4 NM_012193.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.25

Genes affected

FZD4 (HGNC:4042): (frizzled class receptor 4) 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. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]

PRSS23 (HGNC:14370): (serine protease 23) This gene encodes a conserved member of the trypsin family of serine proteases. Mouse studies found a decrease of mRNA levels of this gene after ovulation was induced. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=7 (size 21) in uniprot entity FZD4_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_012193.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_012193.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-86951271-AATCCAC-A is Pathogenic according to our data. Variant chr11-86951271-AATCCAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 5484.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-86951271-AATCCAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4	c.1479_1484delGTGGAT	p.Met493_Trp494del	disruptive_inframe_deletion	Exon 2 of 2	ENST00000531380.2	NP_036325.2
PRSS23	NR_120591.3	n.637_642delCCACAT		non_coding_transcript_exon_variant	Exon 5 of 5
PRSS23	NR_120592.2	n.386_391delCCACAT		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.1479_1484delGTGGAT	p.Met493_Trp494del	disruptive_inframe_deletion	Exon 2 of 2	1	NM_012193.4	ENSP00000434034.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 16, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1479_1484delGTGGAT variant has been published as a pathogenic variant in a large extended family diagnosed with autosomal dominant (Robitaille et al., 2002). In vitro functional studies demonstrated that the c.1479_1484delGTGGAT variant and other disease-causing variants in the FZD4 gene result in a loss-of-function (Robitaille et al., 2002). The c.1479_1484delGTGGAT variant is not observed in large population cohorts (Lek et al., 2016). The c.1479_1484delGTGGAT result in the loss of two conserved amino acid residues. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, this variant is pathogenic. -

Exudative vitreoretinopathy 1 Pathogenic:1

Oct 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs80358301; hg19: chr11-86662313;