3-131462737-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007208.4(MRPL3):c.1033A>G(p.Ile345Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000613 in 1,611,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

MRPL3
NM_007208.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: -0.300

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012210518).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL3	NM_007208.4 linkuse as main transcript	c.1033A>G	p.Ile345Val	missense_variant	10/10	ENST00000264995.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MRPL3	ENST00000264995.8 linkuse as main transcript	c.1033A>G	p.Ile345Val	missense_variant	10/10	1	NM_007208.4	P1
MRPL3	ENST00000425847.6 linkuse as main transcript	c.1114A>G	p.Ile372Val	missense_variant	11/11	2
MRPL3	ENST00000511168.5 linkuse as main transcript	c.1078A>G	p.Ile360Val	missense_variant	10/10	2
MRPL3	ENST00000510043.1 linkuse as main transcript	n.457A>G		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000336

AC:

AN:

249660

Hom.:

AF XY:

0.000326

AC XY:

AN XY:

134930

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000985

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.000549

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000639

AC:

932

AN:

1459038

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

431

AN XY:

725868

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000337

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000699

Gnomad4 FIN exome

AF:

0.0000750

Gnomad4 NFE exome

AF:

0.000799

Gnomad4 OTH exome

AF:

0.000299

GnomAD4 genome

AF:

0.000368

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000580

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000354

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Uncertain significance and reported on 07-13-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 27, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 345 of the MRPL3 protein (p.Ile345Val). This variant is present in population databases (rs143176048, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with MRPL3-related conditions. ClinVar contains an entry for this variant (Variation ID: 425313). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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

Benign

0.063

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.48

Cadd

Benign

0.93

Dann

Benign

0.71

DEOGEN2

Benign

0.054

T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.65

N;N

REVEL

Benign

0.084

Sift

Benign

0.26

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;B

Vest4

0.081

MVP

0.47

MPC

0.058

ClinPred

0.0060

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.28

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