rs80358304

Positions:

• chr11-86951243-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_012193.4(FZD4):​c.1513C>T​(p.Gln505Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FZD4 NM_012193.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.92

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 Pathogenic. Variant got 14 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-86951243-G-A is Pathogenic according to our data. Variant chr11-86951243-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86951243-G-A is described in Lovd as [Pathogenic]. Variant chr11-86951243-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FZD4	NM_012193.4	c.1513C>T	p.Gln505Ter	stop_gained	2/2	ENST00000531380.2
PRSS23	NR_120591.3	n.606G>A		non_coding_transcript_exon_variant	5/5
PRSS23	NR_120592.2	n.355G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FZD4	ENST00000531380.2	c.1513C>T	p.Gln505Ter	stop_gained	2/2	1	NM_012193.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 04, 2022	ClinVar contains an entry for this variant (Variation ID: 449482). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln505*) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the FZD4 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial exudative vitreoretinopathy (PMID: 15223780, 23077402). It has also been observed to segregate with disease in related individuals. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	The Q505X nonsense variant in the FZD4 gene has been reported previously in association with familial exudative vitreoretinopathy (FEVR) (Toomes et al., 2004). This variant is predicted to cause loss of normal protein function through protein truncation, as the final 33 amino acids are lost. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A
Vest4		0.79
GERP RS		6.2

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: rs80358304; hg19: chr11-86662285;