rs147583558
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_002361.4(MAG):c.1394G>A(p.Arg465His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R465C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002361.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAG | NM_002361.4 | c.1394G>A | p.Arg465His | missense_variant | 8/11 | ENST00000392213.8 | |
MAG | NM_001199216.2 | c.1319G>A | p.Arg440His | missense_variant | 8/11 | ||
MAG | NM_080600.3 | c.1394G>A | p.Arg465His | missense_variant | 8/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAG | ENST00000392213.8 | c.1394G>A | p.Arg465His | missense_variant | 8/11 | 1 | NM_002361.4 | P1 | |
MAG | ENST00000537831.2 | c.1319G>A | p.Arg440His | missense_variant | 8/11 | 1 | |||
MAG | ENST00000361922.8 | c.1394G>A | p.Arg465His | missense_variant | 8/12 | 1 | |||
MAG | ENST00000593348.1 | n.231G>A | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250218Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135484
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461516Hom.: 0 Cov.: 34 AF XY: 0.0000303 AC XY: 22AN XY: 727100
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74372
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 75 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 30, 2019 | This sequence change replaces arginine with histidine at codon 465 of the MAG protein (p.Arg465His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs147583558, ExAC 0.02%). This variant has not been reported in the literature in individuals with MAG-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2023 | The c.1394G>A (p.R465H) alteration is located in exon 8 (coding exon 6) of the MAG gene. This alteration results from a G to A substitution at nucleotide position 1394, causing the arginine (R) at amino acid position 465 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at