rs763672163
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_023936.2(MRPS34):c.94C>T(p.Gln32Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,442,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00069 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0013 ( 0 hom. )
Consequence
MRPS34
NM_023936.2 stop_gained
NM_023936.2 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.45
Genes affected
MRPS34 (HGNC:16618): (mitochondrial ribosomal protein S34) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
EME2 (HGNC:27289): (essential meiotic structure-specific endonuclease subunit 2) EME2 forms a heterodimer with MUS81 (MIM 606591) that functions as an XPF (MIM 278760)-type flap/fork endonuclease in DNA repair (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.857 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-1773026-G-A is Pathogenic according to our data. Variant chr16-1773026-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1773026-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MRPS34 | NM_023936.2 | c.94C>T | p.Gln32Ter | stop_gained | 1/3 | ENST00000397375.7 | NP_076425.1 | |
| EME2 | NM_001257370.2 | c.-202G>A | 5_prime_UTR_variant | 1/8 | ENST00000568449.7 | NP_001244299.1 | ||
| MRPS34 | NM_001300900.2 | c.94C>T | p.Gln32Ter | stop_gained | 1/3 | NP_001287829.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MRPS34 | ENST00000397375.7 | c.94C>T | p.Gln32Ter | stop_gained | 1/3 | 1 | NM_023936.2 | ENSP00000380531 | P1 | |
| MRPS34 | ENST00000177742.7 | c.94C>T | p.Gln32Ter | stop_gained | 1/3 | 1 | ENSP00000177742 | |||
| EME2 | ENST00000568449.7 | c.-202G>A | 5_prime_UTR_variant | 1/8 | 1 | NM_001257370.2 | ENSP00000457353 | P1 |
Frequencies
GnomAD3 genomes 0.000692 AC: 105AN: 151798Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.000437 AC: 23AN: 52648Hom.: 0 AF XY: 0.000471 AC XY: 14AN XY: 29696
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GnomAD4 exome AF: 0.00131 AC: 1684AN: 1290104Hom.: 0 Cov.: 61 AF XY: 0.00122 AC XY: 770AN XY: 629498
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GnomAD4 genome 0.000691 AC: 105AN: 151916Hom.: 0 Cov.: 35 AF XY: 0.000700 AC XY: 52AN XY: 74264
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Combined oxidative phosphorylation deficiency 32 Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 27, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID: 28777931, ClinVar ID: 438635] - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 32 (MIM#61766). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0705 - No comparable NMD-predicted variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic or likely pathogenic (ClinVar, LOVD) and has been reported in a single compound heterozygous patient with Leigh's syndrome (PMID: 28777931). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on patient cells found this variant resulted in reduced OXPHOS levels, mitochondrial protein translation and mitochondrial subunit proteins. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 12, 2021 | PVS1, PM3 - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Jan 04, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Apr 16, 2018 | This variant is interpreted as a Likely Pathogenic, for Combined oxidative phosphorylation deficiency 32, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. PM3-Supporting => PM3 downgraded in strength to Supporting (PMID:28777931). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 12, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2024 | Variant summary: MRPS34 c.94C>T (p.Gln32X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00044 in 52648 control chromosomes (gnomAD). c.94C>T has been reported in the literature in individuals affected with Combined Oxidative Phosphorylation Deficiency 32 or Leigh syndrome (Lake_2017, Shen_2023). Western blot analysis using fibroblasts from one patient showed a significant reduction in the MRPS34 protein, as well as reduction in complexes CI and CIV (Lake_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28777931, 35326425, 37385809). ClinVar contains an entry for this variant (Variation ID: 438635). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Gln32*) in the MRPS34 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MRPS34 are known to be pathogenic (PMID: 28777931). This variant is present in population databases (rs763672163, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Leigh syndrome, transient metabolic acidosis and hemodynamic instability related to tubulopathy (PMID: 28777931). ClinVar contains an entry for this variant (Variation ID: 438635). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28777931, 30358850, 30566640, 35326425, 37385809) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at