rs2042643133

Variant names:

• chr16-1772831-G-A
• rs2042643133
• NM_023936.2:c.289C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023936.2(MRPS34):​c.289C>T​(p.Leu97Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30148208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS34	NM_023936.2	c.289C>T	p.Leu97Phe	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2	c.-397G>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2	c.289C>T	p.Leu97Phe	missense_variant	Exon 1 of 3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS34	ENST00000397375.7	c.289C>T	p.Leu97Phe	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.289C>T	p.Leu97Phe	missense_variant	Exon 1 of 3	1		ENSP00000177742.3
EME2	ENST00000568449	c.-397G>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 63

GnomAD4 genome Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Uncertain:1

May 22, 2023

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MPRS34 c.289C>T (p.Leu97Phe) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, c.289C>T (p.Leu97Phe) variant is classified as a variant of uncertain significance for primary mitochondrial disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.96	D;D
Vest4		0.33
MutPred		0.39		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.085
MPC		2.8
ClinPred		0.92	D
GERP RS		3.7
Varity_R		0.27
gMVP		0.79

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

Other links and lift over

dbSNP: rs2042643133; hg19: chr16-1822832;