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GeneBe

19-38932422-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_033362.4(MRPS12):c.139C>T(p.Arg47Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,610,040 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: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MRPS12
NM_033362.4 missense

Scores

7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.475
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21572575).
BS2
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MRPS12NM_033362.4 linkuse as main transcriptc.139C>T p.Arg47Trp missense_variant 3/3 ENST00000308018.9
MRPS12NM_021107.1 linkuse as main transcriptc.139C>T p.Arg47Trp missense_variant 2/2
MRPS12NM_033363.1 linkuse as main transcriptc.139C>T p.Arg47Trp missense_variant 3/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MRPS12ENST00000308018.9 linkuse as main transcriptc.139C>T p.Arg47Trp missense_variant 3/31 NM_033362.4 P1
MRPS12ENST00000402029.3 linkuse as main transcriptc.139C>T p.Arg47Trp missense_variant 3/31 P1
MRPS12ENST00000407800.2 linkuse as main transcriptc.139C>T p.Arg47Trp missense_variant 2/21 P1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000202
AC:
5
AN:
247320
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
134238
show subpopulations
Gnomad AFR exome
AF:
0.0000636
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000328
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000269
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000110
AC:
160
AN:
1457826
Hom.:
0
Cov.:
31
AF XY:
0.000116
AC XY:
84
AN XY:
724718
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000137
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000603
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 06, 2022The c.139C>T (p.R47W) alteration is located in exon 3 (coding exon 2) of the MRPS12 gene. This alteration results from a C to T substitution at nucleotide position 139, causing the arginine (R) at amino acid position 47 to be replaced by a tryptophan (W). 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
0.16
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.53
Cadd
Benign
13
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.49
T;T;T
Eigen
Benign
-0.97
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.12
N
M_CAP
Uncertain
0.090
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.4
M;M;M
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Uncertain
-3.9
D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.0030
D;D;D
Polyphen
0.98
D;D;D
Vest4
0.23
MVP
0.40
MPC
1.1
ClinPred
0.95
D
GERP RS
-12
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.060
gMVP
0.31

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772487012; hg19: chr19-39423062; COSMIC: COSV55498188; COSMIC: COSV55498188; API