rs80358301

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV000566543: "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)."".

• 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
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000566543: "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)."
• 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 VariationId is 5484.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012193.4. 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
	FZD4	NM_012193.4	MANE Select	c.1479_1484delGTGGAT	p.Met493_Trp494del	disruptive_inframe_deletion	Exon 2 of 2	NP_036325.2
	PRSS23	NR_120591.3		n.637_642delCCACAT		non_coding_transcript_exon	Exon 5 of 5
	PRSS23	NR_120592.2		n.386_391delCCACAT		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD4	ENST00000531380.2	TSL:1 MANE Select	c.1479_1484delGTGGAT	p.Met493_Trp494del	disruptive_inframe_deletion	Exon 2 of 2	ENSP00000434034.1	Q9ULV1
	PRSS23	ENST00000532234.5	TSL:1	n.*267_*272delCCACAT		non_coding_transcript_exon	Exon 5 of 5	ENSP00000436676.1	E9PIB7
	PRSS23	ENST00000532234.5	TSL:1	n.*267_*272delCCACAT		3_prime_UTR	Exon 5 of 5	ENSP00000436676.1	E9PIB7

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Exudative vitreoretinopathy 1 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs80358301; hg19: chr11-86662313;