NM_023936.2:c.519G>C

Variant names:

• chr16-1772359-C-G
• rs1173682229
• NM_023936.2:c.519G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_023936.2(MRPS34):​c.519G>C​(p.Met173Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,460,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MRPS34 NM_023936.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21706137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS34	NM_023936.2	c.519G>C	p.Met173Ile	missense_variant	Exon 3 of 3	ENST00000397375.7	NP_076425.1
MRPS34	NM_001300900.2	c.540G>C	p.Met180Ile	missense_variant	Exon 3 of 3		NP_001287829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS34	ENST00000397375.7	c.519G>C	p.Met173Ile	missense_variant	Exon 3 of 3	1	NM_023936.2	ENSP00000380531.3
MRPS34	ENST00000177742.7	c.540G>C	p.Met180Ile	missense_variant	Exon 3 of 3	1		ENSP00000177742.3
MRPS34	ENST00000569585.1	n.250G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250088 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135644

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: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460642 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 180 of the MRPS34 protein (p.Met180Ile). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MRPS34-related conditions. ClinVar contains an entry for this variant (Variation ID: 1361821). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.043	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.14
Sift	Benign	0.090	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	B;B
Vest4		0.48
MutPred		0.68		Loss of disorder (P = 0.0733);.;
MVP		0.072
MPC		0.18
ClinPred		0.17	T
GERP RS		2.1
Varity_R		0.17
gMVP		0.73

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: rs1173682229; hg19: chr16-1822360;