21-41377912-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002463.2(MX2):c.373G>A(p.Gly125Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002463.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MX2 | NM_002463.2 | c.373G>A | p.Gly125Arg | missense_variant | 3/14 | ENST00000330714.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MX2 | ENST00000330714.8 | c.373G>A | p.Gly125Arg | missense_variant | 3/14 | 1 | NM_002463.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251304Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135854
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461848Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727230
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152350Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74496
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2024 | The c.373G>A (p.G125R) alteration is located in exon 3 (coding exon 2) of the MX2 gene. This alteration results from a G to A substitution at nucleotide position 373, causing the glycine (G) at amino acid position 125 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 20, 2020 | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MX2-related conditions. This variant is present in population databases (rs527335705, ExAC 0.07%). This sequence change replaces glycine with arginine at codon 125 of the MX2 protein (p.Gly125Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at