rs119478059
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_020191.4(MRPS22):c.509G>A(p.Arg170His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170C) has been classified as Uncertain significance.
Frequency
Consequence
NM_020191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MRPS22 | NM_020191.4 | c.509G>A | p.Arg170His | missense_variant | 4/8 | ENST00000680020.1 | |
MRPS22 | NM_001363893.1 | c.506G>A | p.Arg169His | missense_variant | 4/8 | ||
MRPS22 | NM_001363857.1 | c.386G>A | p.Arg129His | missense_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MRPS22 | ENST00000680020.1 | c.509G>A | p.Arg170His | missense_variant | 4/8 | NM_020191.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251196Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135756
GnomAD4 exome AF: 0.000144 AC: 211AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98AN XY: 727216
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74308
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2023 | 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: 18539099, 29096039, 31683770, 17873122, 31589614, 33917098, 33314036, 27535533) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | This sequence change replaces arginine with histidine at codon 170 of the MRPS22 protein (p.Arg170His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs119478059, ExAC 0.01%). This missense change has been observed in individual(s) with MRPS22-related disease (PMID: 29096039; 17873122and29096039). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4753). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MRPS22 function (PMID: 17873122, 18539099). For these reasons, this variant has been classified as Pathogenic. - |
Hypotonia with lactic acidemia and hyperammonemia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 01, 2019 | This variant was observed in compound heterozygosity with variant c.480_481insA - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Hypotonia with lactic acidemia and hyperammonemia;C4748263:Ovarian dysgenesis 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 22, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at