rs201229537

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_016034.5(MRPS2):c.340G>A(p.Asp114Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

MRPS2
NM_016034.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 8.63

Variant links:

Genes affected

MRPS2 (HGNC:14495): (mitochondrial ribosomal protein S2) 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 28S subunit protein that belongs to the ribosomal protein S2 family. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

MRPS2 links:

(HGNC:):

links:

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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;

PP5

Variant 9-135503582-G-A is Pathogenic according to our data. Variant chr9-135503582-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523224.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr9-135503582-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.32183754).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS2	NM_016034.5 linkuse as main transcript	c.340G>A	p.Asp114Asn	missense_variant	4/4	ENST00000241600.10
LOC101928525	NR_121579.1 linkuse as main transcript	n.808C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS2	ENST00000241600.10 linkuse as main transcript	c.340G>A	p.Asp114Asn	missense_variant	4/4	1	NM_016034.5	P1
	ENST00000415062.1 linkuse as main transcript	n.808C>T		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000838

AC:

AN:

250726

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000707

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461412

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation deficiency 36

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 03, 2018	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Pathogenic, for Combined oxidative phosphorylation deficiency 36, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (https://www.ncbi.nlm.nih.gov/pubmed/29576219). PS3-Very Strong => PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/29576219). -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 28, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 114 of the MRPS2 protein (p.Asp114Asn). This variant is present in population databases (rs201229537, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 29576219). ClinVar contains an entry for this variant (Variation ID: 523224). 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 MRPS2 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

Pathogenic

0.66

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.065

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.3

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.82

MVP

0.50

MPC

0.78

ClinPred

0.54

GERP RS

3.7

Varity_R

0.29

gMVP

0.85

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