rs80358303
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000531380.2(FZD4):c.1501_1502del(p.Leu501SerfsTer33) 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 (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
FZD4
ENST00000531380.2 frameshift
ENST00000531380.2 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 9 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-86951253-AAG-A is Pathogenic according to our data. Variant chr11-86951253-AAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-86951253-AAG-A is described in Lovd as [Pathogenic]. Variant chr11-86951253-AAG-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FZD4 | NM_012193.4 | c.1501_1502del | p.Leu501SerfsTer33 | frameshift_variant | 2/2 | ENST00000531380.2 | NP_036325.2 | |
PRSS23 | NR_120591.3 | n.619_620del | non_coding_transcript_exon_variant | 5/5 | ||||
PRSS23 | NR_120592.2 | n.368_369del | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FZD4 | ENST00000531380.2 | c.1501_1502del | p.Leu501SerfsTer33 | frameshift_variant | 2/2 | 1 | NM_012193.4 | ENSP00000434034 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 05, 2023 | This sequence change creates a premature translational stop signal (p.Leu501Serfs*33) in the FZD4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 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 individual(s) with clinical features of familial exudative vitreoretinopathy (PMID: 12172548, 31999491). This variant is also known as L501fsX533. ClinVar contains an entry for this variant (Variation ID: 5485). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FZD4 function (PMID: 24036468, 31999491). This variant disrupts a region of the FZD4 protein in which other variant(s) (p.Thr503Valfs*31) have been determined to be pathogenic (PMID: 21097938, 25711638). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 12, 2021 | Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31999491, 12172548, 24036468, 20340138) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Exudative vitreoretinopathy 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | DBGen Ocular Genomics | Jan 01, 2022 | Class 5 ACMG Guidelines, 2015 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 06, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000005485). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
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Calibrated prediction
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at