rs771914518

Variant names:

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

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]

MRPL3 links:

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 rank	MANE	Protein	UniProt
MRPL3	NM_007208.4 link	c.824G>A	p.Arg275Lys	missense_variant	Exon 9 of 10	ENST00000264995.8	NP_009139.1	P09001

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRPL3	ENST00000264995.8 link	c.824G>A	p.Arg275Lys	missense_variant	Exon 9 of 10	1	NM_007208.4	ENSP00000264995.2	P09001
MRPL3	ENST00000425847.6 link	c.905G>A	p.Arg302Lys	missense_variant	Exon 10 of 11	2		ENSP00000398536.2	E7ETU7
MRPL3	ENST00000511168.5 link	c.866G>A	p.Arg289Lys	missense_variant	Exon 9 of 10	2		ENSP00000424107.1	H0Y9G6
MRPL3	ENST00000510043.1 link	n.248G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151822

Hom.:

Cov.:

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:

AN:

224464

Hom.:

AF XY:

0.0000246

AC XY:

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:

AN:

1430292

Hom.:

Cov.:

AF XY:

0.00000844

AC XY:

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:

AN:

151822

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

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.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Aug 30, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.63

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over