NM_001257370.2:c.-266C>T

Variant names:

• chr16-1772962-C-T
• rs1452885468
• NM_001257370.2:c.-266C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001257370.2(EME2):​c.-266C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,296,724 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: EME2 NM_001257370.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87
• Publications: 0 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 32

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26483506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EME2	NM_001257370.2	c.-266C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_023936.2	c.158G>A	p.Arg53Gln	missense_variant	Exon 1 of 3	ENST00000397375.7	NP_076425.1
EME2	NM_001257370.2	c.-266C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000568449.7	NP_001244299.1
MRPS34	NM_001300900.2	c.158G>A	p.Arg53Gln	missense_variant	Exon 1 of 3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EME2	ENST00000568449.7	c.-266C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1
MRPS34	ENST00000397375.7	c.158G>A	p.Arg53Gln	missense_variant	Exon 1 of 3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.158G>A	p.Arg53Gln	missense_variant	Exon 1 of 3	1		ENSP00000177742.3
EME2	ENST00000568449.7	c.-266C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_001257370.2	ENSP00000457353.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1296724 Hom.: 0 Cov.: 62 AF XY: 0.00000158 AC XY: 1 AN XY: 634208

African (AFR) AF: 0.00 AC: 0 AN: 25322

American (AMR) AF: 0.00 AC: 0 AN: 20498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19426

East Asian (EAS) AF: 0.00 AC: 0 AN: 30870

South Asian (SAS) AF: 0.00 AC: 0 AN: 65878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 9.65e-7 AC: 1 AN: 1036230

Other (OTH) AF: 0.00 AC: 0 AN: 53514

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158G>A (p.R53Q) alteration is located in exon 1 (coding exon 1) of the MRPS34 gene. This alteration results from a G to A substitution at nucleotide position 158, causing the arginine (R) at amino acid position 53 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	0.018
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	.;M
PhyloP100		1.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.063
Sift	Benign	0.16	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.96	D;D
Vest4		0.24
MutPred		0.25		Loss of MoRF binding (P = 0.0338);Loss of MoRF binding (P = 0.0338);
MVP		0.41
MPC		3.0
ClinPred		0.87	D
GERP RS		2.7
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.033
gMVP		0.71

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

Other links and lift over

dbSNP: rs1452885468; hg19: chr16-1822963;