19-38932427-G-T

Variant names:

• chr19-38932427-G-T
• rs771322318
• NM_033362.4:c.144G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033362.4(MRPS12):​c.144G>T​(p.Lys48Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K48R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MRPS12 NM_033362.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.10

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.081559).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS12	NM_033362.4	c.144G>T	p.Lys48Asn	missense_variant	Exon 3 of 3	ENST00000308018.9	NP_203526.1
MRPS12	NM_021107.1	c.144G>T	p.Lys48Asn	missense_variant	Exon 2 of 2		NP_066930.1
MRPS12	NM_033363.1	c.144G>T	p.Lys48Asn	missense_variant	Exon 3 of 3		NP_203527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS12	ENST00000308018.9	c.144G>T	p.Lys48Asn	missense_variant	Exon 3 of 3	1	NM_033362.4	ENSP00000308845.3
MRPS12	ENST00000402029.3	c.144G>T	p.Lys48Asn	missense_variant	Exon 3 of 3	1		ENSP00000384579.2
MRPS12	ENST00000407800.2	c.144G>T	p.Lys48Asn	missense_variant	Exon 2 of 2	1		ENSP00000384952.1
ENSG00000269547	ENST00000599996.1	c.475-6127C>A		intron_variant	Intron 5 of 19	2		ENSP00000472465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248334 AF XY: 0.0000149

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458604 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 725186

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33428

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44566

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26074

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39626

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86180

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52738

Gnomad4 NFE exome AF: 0.00000180 AC: 2 AN: 1109998

Gnomad4 Remaining exome AF: 0.0000498 AC: 3 AN: 60240

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.144G>T (p.K48N) alteration is located in exon 3 (coding exon 2) of the MRPS12 gene. This alteration results from a G to T substitution at nucleotide position 144, causing the lysine (K) at amino acid position 48 to be replaced by an asparagine (N). 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	0.27
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0060
DANN	Benign	0.79
DEOGEN2	Benign	0.17	T;T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.057	N
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.096	B;B;B
Vest4		0.14
MutPred		0.53		Loss of methylation at K48 (P = 0.0075);Loss of methylation at K48 (P = 0.0075);Loss of methylation at K48 (P = 0.0075);
MVP		0.22
MPC		0.77
ClinPred		0.082	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.043
gMVP		0.38
Mutation Taster		=84/16	polymorphism

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: rs771322318; hg19: chr19-39423067;