rs80358285
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Moderate
The ENST00000531380.2(FZD4):c.314T>C(p.Met105Thr) variant causes a missense 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M105V) has been classified as Pathogenic.
Frequency
Consequence
ENST00000531380.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FZD4 | NM_012193.4 | c.314T>C | p.Met105Thr | missense_variant | 2/2 | ENST00000531380.2 | NP_036325.2 | |
PRSS23 | NR_120591.3 | n.1805A>G | non_coding_transcript_exon_variant | 5/5 | ||||
PRSS23 | NR_120592.2 | n.1554A>G | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FZD4 | ENST00000531380.2 | c.314T>C | p.Met105Thr | missense_variant | 2/2 | 1 | NM_012193.4 | ENSP00000434034 | P1 | |
PRSS23 | ENST00000532234.5 | c.*1435A>G | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 1 | ENSP00000436676 | ||||
PRSS23 | ENST00000533902.2 | c.*1157A>G | 3_prime_UTR_variant | 3/3 | 4 | ENSP00000437268 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 20, 2023 | Experimental studies have shown that this missense change affects FZD4 function (PMID: 24744206). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FZD4 protein function. This missense change has been observed in individual(s) with familial exudative vitreoretinopathy (PMID: 15223780). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 105 of the FZD4 protein (p.Met105Thr). This variant disrupts the p.Met105 amino acid residue in FZD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14507768, 17955262, 24744206, 30452590, 31294129). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at