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GeneBe

3-131468161-C-T

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

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.94
Variant links:
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]

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
MRPL3NM_007208.4 linkuse as main transcriptc.824G>A p.Arg275Lys missense_variant 9/10 ENST00000264995.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MRPL3ENST00000264995.8 linkuse as main transcriptc.824G>A p.Arg275Lys missense_variant 9/101 NM_007208.4 P1
MRPL3ENST00000425847.6 linkuse as main transcriptc.905G>A p.Arg302Lys missense_variant 10/112
MRPL3ENST00000511168.5 linkuse as main transcriptc.869G>A p.Arg290Lys missense_variant 9/102
MRPL3ENST00000510043.1 linkuse as main transcriptn.248G>A non_coding_transcript_exon_variant 3/42

Frequencies

GnomAD3 genomes
AF:
0.0000790
AC:
12
AN:
151822
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000312
AC:
7
AN:
224464
Hom.:
0
AF XY:
0.0000246
AC XY:
3
AN XY:
121926
show subpopulations
Gnomad AFR exome
AF:
0.000335
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000189
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000147
AC:
21
AN:
1430292
Hom.:
0
Cov.:
29
AF XY:
0.00000844
AC XY:
6
AN XY:
711304
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000375
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000146
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
AF:
0.0000790
AC:
12
AN:
151822
Hom.:
0
Cov.:
32
AF XY:
0.0000944
AC XY:
7
AN XY:
74128
show subpopulations
Gnomad4 AFR
AF:
0.000145
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:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingGeneDxAug 30, 2022In 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 submitterclinical testingInvitaeOct 31, 2022This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.25
Cadd
Pathogenic
27
Dann
Uncertain
0.99
DEOGEN2
Benign
0.19
T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.020
T
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Benign
0.19
Sift
Benign
0.031
D;D
Sift4G
Benign
0.10
T;T
Polyphen
0.75
P;B
Vest4
0.88
MutPred
0.59
.;Gain of methylation at R302 (P = 0.0365);
MVP
0.70
MPC
0.31
ClinPred
0.36
T
GERP RS
5.4
Varity_R
0.91
gMVP
0.73

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: rs771914518; hg19: chr3-131187005; API