rs563189672
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_023936.2(MRPS34):c.322-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,604,034 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 Pathogenic (★★).
Frequency
Consequence
NM_023936.2 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MRPS34 | ENST00000397375.7 | c.322-10G>A | intron_variant | Intron 1 of 2 | 1 | NM_023936.2 | ENSP00000380531.3 | |||
MRPS34 | ENST00000177742.7 | c.322-10G>A | intron_variant | Intron 1 of 2 | 1 | ENSP00000177742.3 | ||||
MRPS34 | ENST00000569585.1 | n.43G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152266Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000836 AC: 2AN: 239276Hom.: 0 AF XY: 0.00000761 AC XY: 1AN XY: 131324
GnomAD4 exome AF: 0.00000758 AC: 11AN: 1451650Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4AN XY: 722530
GnomAD4 genome AF: 0.000151 AC: 23AN: 152384Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74518
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation deficiency 32 Pathogenic:4
Variant summary: MRPS34 c.322-10G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the 3' canonical acceptor site. One predict the variant weakens the 3' canonical acceptor site. Four predict the variant creates a 3' cryptic acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by producing abnormal transcripts that result in frameshift and premature truncation, respectively (Lake_2017). The variant allele was found at a frequency of 8.4e-06 in 239276 control chromosomes. c.322-10G>A has been reported at a homozygous state in multiple individuals affected with Leigh Syndrome (examples, MartinSaavedra_2021, Alves_2020, Lake_2017). These data indicate that the variant is very likely to be associated with Combined Oxidative Phosphorylation Deficiency 32. The following publications have been ascertained in the context of this evaluation (PMID: 32445240, 28777931, 34052969). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:2
This sequence change falls in intron 1 of the MRPS34 gene. It does not directly change the encoded amino acid sequence of the MRPS34 protein. This variant is present in population databases (rs563189672, gnomAD 0.006%). This variant has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 28777931). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438633). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate abnormal splicing resulting in a frameshift and premature truncation with 75% reduction in transcript level (Lake et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28777931, 33314036, 30358850, 32445240) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at