rs763672163

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.45

Variant links:

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]

MRPS34 links:

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]

EME2 links:

Genome browser will be placed here

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. There are 6 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
MRPS34	NM_023936.2 linkuse as main transcript	c.94C>T	p.Gln32Ter	stop_gained	1/3	ENST00000397375.7
EME2	NM_001257370.2 linkuse as main transcript	c.-202G>A		5_prime_UTR_variant	1/8	ENST00000568449.7
MRPS34	NM_001300900.2 linkuse as main transcript	c.94C>T	p.Gln32Ter	stop_gained	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS34	ENST00000397375.7 linkuse as main transcript	c.94C>T	p.Gln32Ter	stop_gained	1/3	1	NM_023936.2	P1
MRPS34	ENST00000177742.7 linkuse as main transcript	c.94C>T	p.Gln32Ter	stop_gained	1/3	1
EME2	ENST00000568449.7 linkuse as main transcript	c.-202G>A		5_prime_UTR_variant	1/8	1	NM_001257370.2	P1	A4GXA9-1

Frequencies

GnomAD3 genomes

AF:

0.000692

AC:

105

AN:

151798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00133

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000437

AC:

AN:

52648

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

29696

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000213

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00131

AC:

1684

AN:

1290104

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

770

AN XY:

629498

show subpopulations

Gnomad4 AFR exome

AF:

0.000198

Gnomad4 AMR exome

AF:

0.000104

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000156

Gnomad4 FIN exome

AF:

0.000236

Gnomad4 NFE exome

AF:

0.00159

Gnomad4 OTH exome

AF:

0.000546

GnomAD4 genome

AF:

0.000691

AC:

105

AN:

151916

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00133

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00234

AC:

ExAC

AF:

0.000212

AC:

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	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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2022	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 0.00046 in 83970 control chromosomes (gnomAD). c.94C>T has been reported in the literature as a biallelic genotype in at least one individual affected with Leigh syndrome (Lake_2017). Western blot analysis using fibroblasts from this same patient showed a significant reduction in the MRPS34 protein, as well as reduction in complexes CI and CIV (Lake_2017). Nine ClinVar submitters have assessed the variant since 2014: four classified the variant as likely pathogenic, and five as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 15, 2017	- -
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	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	May 12, 2021	PVS1, PM3 -
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] -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	- -

Ataxia-telangiectasia syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2024

Variant summary: ATM c.94C>T (p.Arg32Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage (IPR021668) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251158 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.8e-05 vs 0.004), allowing no conclusion about variant significance. c.94C>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 142913). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.59

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.54

MutationTaster

Benign

1.0

A;A;A

Vest4

0.17

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over