3-131468161-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_007208.4(MRPL3):c.824G>A(p.Arg275Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000209 in 1,582,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
MRPL3
NM_007208.4 missense
NM_007208.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 6.94
Genes affected
MRPL3 (HGNC:10379): (mitochondrial ribosomal protein L3) 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 that belongs to the L3P ribosomal protein family. A pseudogene corresponding to this gene is found on chromosome 13q. [provided by RefSeq, Jul 2008]
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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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MRPL3 | NM_007208.4 | c.824G>A | p.Arg275Lys | missense_variant | 9/10 | ENST00000264995.8 | NP_009139.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MRPL3 | ENST00000264995.8 | c.824G>A | p.Arg275Lys | missense_variant | 9/10 | 1 | NM_007208.4 | ENSP00000264995 | P1 | |
MRPL3 | ENST00000425847.6 | c.905G>A | p.Arg302Lys | missense_variant | 10/11 | 2 | ENSP00000398536 | |||
MRPL3 | ENST00000511168.5 | c.869G>A | p.Arg290Lys | missense_variant | 9/10 | 2 | ENSP00000424107 | |||
MRPL3 | ENST00000510043.1 | n.248G>A | non_coding_transcript_exon_variant | 3/4 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000790 AC: 12AN: 151822Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000312 AC: 7AN: 224464Hom.: 0 AF XY: 0.0000246 AC XY: 3AN XY: 121926
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GnomAD4 exome AF: 0.0000147 AC: 21AN: 1430292Hom.: 0 Cov.: 29 AF XY: 0.00000844 AC XY: 6AN XY: 711304
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GnomAD4 genome AF: 0.0000790 AC: 12AN: 151822Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7AN XY: 74128
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 31, 2022 | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 275 of the MRPL3 protein (p.Arg275Lys). This variant is present in population databases (rs771914518, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MRPL3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MRPL3 protein function. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
P;B
Vest4
MutPred
0.59
.;Gain of methylation at R302 (P = 0.0365);
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at