rs863225213
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_003611.3(OFD1):āc.149A>Gā(p.His50Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,359 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H50Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_003611.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OFD1 | NM_003611.3 | c.149A>G | p.His50Arg | missense_variant | 3/23 | ENST00000340096.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OFD1 | ENST00000340096.11 | c.149A>G | p.His50Arg | missense_variant | 3/23 | 1 | NM_003611.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000896 AC: 1AN: 111584Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33788
GnomAD4 exome AF: 0.0000146 AC: 16AN: 1097775Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 4AN XY: 363135
GnomAD4 genome ? AF: 0.00000896 AC: 1AN: 111584Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33788
ClinVar
Submissions by phenotype
Joubert syndrome 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | UW Hindbrain Malformation Research Program, University of Washington | Feb 23, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 08, 2022 | Identified in a patient with Joubert syndrome in published literature (Bachmann-Gagescu et al., 2015; Vilboux et al., 2017; Pezzella et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28125082, 35112477, 26092869) - |
Familial aplasia of the vermis;C1510460:Orofaciodigital syndrome I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 07, 2023 | ClinVar contains an entry for this variant (Variation ID: 217687). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) performed at Invitae indicates that this missense variant is not expected to disrupt OFD1 protein function. This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 50 of the OFD1 protein (p.His50Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at