rs202219398
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_004208.4(AIFM1):c.1388G>T(p.Arg463Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,209,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004208.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AIFM1 | NM_004208.4 | c.1388G>T | p.Arg463Ile | missense_variant | 13/16 | ENST00000287295.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AIFM1 | ENST00000287295.8 | c.1388G>T | p.Arg463Ile | missense_variant | 13/16 | 1 | NM_004208.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000108 AC: 12AN: 110912Hom.: 0 Cov.: 21 AF XY: 0.0000906 AC XY: 3AN XY: 33098
GnomAD3 exomes AF: 0.000185 AC: 34AN: 183468Hom.: 0 AF XY: 0.000133 AC XY: 9AN XY: 67902
GnomAD4 exome AF: 0.000238 AC: 261AN: 1098110Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 70AN XY: 363466
GnomAD4 genome ? AF: 0.000108 AC: 12AN: 110912Hom.: 0 Cov.: 21 AF XY: 0.0000906 AC XY: 3AN XY: 33098
ClinVar
Submissions by phenotype
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Mar 12, 2021 | Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. - |
Charcot-Marie-Tooth disease X-linked recessive 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | Likely pathogenic based on conservation and prediction scores (Phylop, Polyphen, SIFT, MutationTaster) and consistent with neuropathy of patient. Patient also had Sotos syndrome with de novo frameshift insertion in NSD1 - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2021 | This variant is associated with the following publications: (PMID: 26257172, 32376792) - |
Combined oxidative phosphorylation deficiency;CN118851:Charcot-Marie-Tooth Neuropathy X Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at