NM_033362.4:c.40C>G

Variant names:

• chr19-38931334-C-G
• rs1974745664
• NM_033362.4:c.40C>G

Variant summary

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

The NM_033362.4(MRPS12):​c.40C>G​(p.Leu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MRPS12 NM_033362.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

Genes affected

MRPS12 (HGNC:10380): (mitochondrial ribosomal protein S12) 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 that belongs to the ribosomal protein S12P family. The encoded protein is a key component of the ribosomal small subunit and controls the decoding fidelity and susceptibility to aminoglycoside antibiotics. The gene for mitochondrial seryl-tRNA synthetase is located upstream and adjacent to this gene, and both genes are possible candidates for the autosomal dominant deafness gene (DFNA4). Splice variants that differ in the 5' UTR have been found for this gene; all three variants encode the same protein. [provided by RefSeq, Jul 2008]

ENSG00000269547 (HGNC:):

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=0.08366233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS12	NM_033362.4	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 3	ENST00000308018.9	NP_203526.1
MRPS12	NM_021107.1	c.40C>G	p.Leu14Val	missense_variant	Exon 1 of 2		NP_066930.1
MRPS12	NM_033363.1	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 3		NP_203527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS12	ENST00000308018.9	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 3	1	NM_033362.4	ENSP00000308845.3
ENSG00000269547	ENST00000599996.1	c.475-5034G>C		intron_variant	Intron 5 of 19	2		ENSP00000472465.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448172 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 720760

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40C>G (p.L14V) alteration is located in exon 2 (coding exon 1) of the MRPS12 gene. This alteration results from a C to G substitution at nucleotide position 40, causing the leucine (L) at amino acid position 14 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.091	T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.41	N
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.13
MutPred		0.37		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP		0.49
MPC		0.45
ClinPred		0.093	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1974745664; hg19: chr19-39421974;