17-81703574-A-G

Variant summary

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

The NM_002949.4(MRPL12):ā€‹c.73A>Gā€‹(p.Arg25Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,440,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

MRPL12
NM_002949.4 missense, splice_region

Scores

1
7
10
Splicing: ADA: 0.9992
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93
Variant links:
Genes affected
MRPL12 (HGNC:10378): (mitochondrial ribosomal protein L12) 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 39S subunit protein which forms homodimers. In prokaryotic ribosomes, two L7/L12 dimers and one L10 protein form the L8 protein complex. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MRPL12NM_002949.4 linkuse as main transcriptc.73A>G p.Arg25Gly missense_variant, splice_region_variant 1/5 ENST00000333676.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MRPL12ENST00000333676.8 linkuse as main transcriptc.73A>G p.Arg25Gly missense_variant, splice_region_variant 1/51 NM_002949.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000621
AC:
8
AN:
1288414
Hom.:
0
Cov.:
31
AF XY:
0.00000633
AC XY:
4
AN XY:
631832
show subpopulations
Gnomad4 AFR exome
AF:
0.000311
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.0000115
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 22, 2022This variant is present in population databases (rs767111957, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MRPL12-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 25 of the MRPL12 protein (p.Arg25Gly). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.052
T;.
Eigen
Benign
0.13
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.71
T;T
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
0.84
D;N
PROVEAN
Benign
-2.2
N;.
REVEL
Benign
0.24
Sift
Uncertain
0.020
D;.
Sift4G
Uncertain
0.029
D;D
Polyphen
0.40
B;.
Vest4
0.39
MutPred
0.34
Gain of methylation at R22 (P = 0.0418);Gain of methylation at R22 (P = 0.0418);
MVP
0.91
MPC
0.89
ClinPred
0.95
D
GERP RS
4.7
Varity_R
0.28
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.040
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: rs767111957; hg19: chr17-79670604; API