rs1057522195
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_006796.3(AFG3L2):c.1064C>T(p.Thr355Met) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T355T) has been classified as Likely benign.
Frequency
Consequence
NM_006796.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AFG3L2 | NM_006796.3 | c.1064C>T | p.Thr355Met | missense_variant | 9/17 | ENST00000269143.8 | |
AFG3L2 | XM_011525601.4 | c.1064C>T | p.Thr355Met | missense_variant | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AFG3L2 | ENST00000269143.8 | c.1064C>T | p.Thr355Met | missense_variant | 9/17 | 1 | NM_006796.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 22, 2023 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32219868, 36974169, 36110148) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 24, 2023 | For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt AFG3L2 protein function. ClinVar contains an entry for this variant (Variation ID: 385335). This missense change has been observed in individuals with clinical features of autosomal dominant AFG3L2-related conditions (PMID: 32219868; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 355 of the AFG3L2 protein (p.Thr355Met). - |
Dystonic disorder;C0029124:Optic atrophy;C1866129:Abnormal cerebellum morphology;C3887506:Hyperkinetic movements Pathogenic:1
Pathogenic, no assertion criteria provided | research | Neurogenetics, IRCCS Istituto delle Scienze Neurologiche di Bologna | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 10, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at