Genetic Variant MRPS2:p.Thr30Asn (chr9-135501043-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016034.5(MRPS2):c.89C>A(p.Thr30Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,610,904 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 33)

Exomes 𝑓: 0.014 ( 210 hom. )

Consequence

MRPS2
NM_016034.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.457

Publications

5 publications found

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:

PIERCE1 (HGNC:28435): (piercer of microtubule wall 1) Predicted to act upstream of or within several processes, including cellular response to DNA damage stimulus; cellular response to UV-C; and determination of left/right symmetry. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PIERCE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002593249).

BP6

Variant 9-135501043-C-A is Benign according to our data. Variant chr9-135501043-C-A is described in ClinVar as Benign. ClinVar VariationId is 1601052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1729/152188) while in subpopulation NFE AF = 0.0161 (1098/67996). AF 95% confidence interval is 0.0154. There are 17 homozygotes in GnomAd4. There are 790 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016034.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPS2	NM_016034.5	MANE Select	c.89C>A	p.Thr30Asn	missense	Exon 2 of 4	NP_057118.1	Q9Y399
MRPS2	NM_001371401.1		c.89C>A	p.Thr30Asn	missense	Exon 3 of 5	NP_001358330.1	Q9Y399
MRPS2	NR_051967.3		n.118C>A		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRPS2	ENST00000241600.10	TSL:1 MANE Select	c.89C>A	p.Thr30Asn	missense	Exon 2 of 4	ENSP00000241600.5	Q9Y399
PIERCE1	ENST00000371791.5	TSL:1	c.-65+586G>T		intron	N/A	ENSP00000360856.1	Q5BN46-2
MRPS2	ENST00000371785.5	TSL:3	c.89C>A	p.Thr30Asn	missense	Exon 3 of 5	ENSP00000360850.1	Q9Y399

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1733

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.0403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0134

AC:

3200

AN:

238800

AF XY:

0.0136

show subpopulations

Gnomad AFR exome

AF:

0.00218

Gnomad AMR exome

AF:

0.0178

Gnomad ASJ exome

AF:

0.0407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00366

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0144

AC:

21070

AN:

1458716

Hom.:

210

Cov.:

AF XY:

0.0143

AC XY:

10351

AN XY:

725634

show subpopulations

African (AFR)

AF:

0.00371

AC:

124

AN:

33428

American (AMR)

AF:

0.0181

AC:

807

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.0424

AC:

1105

AN:

26058

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39642

South Asian (SAS)

AF:

0.00551

AC:

475

AN:

86130

European-Finnish (FIN)

AF:

0.00348

AC:

180

AN:

51692

Middle Eastern (MID)

AF:

0.0332

AC:

191

AN:

5750

European-Non Finnish (NFE)

AF:

0.0154

AC:

17129

AN:

1111206

Other (OTH)

AF:

0.0176

AC:

1057

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1240

2480

3719

4959

6199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

648

1296

1944

2592

3240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0114

AC:

1729

AN:

152188

Hom.:

Cov.:

AF XY:

0.0106

AC XY:

790

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41524

American (AMR)

AF:

0.0148

AC:

227

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0403

AC:

140

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00436

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00443

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1098

AN:

67996

Other (OTH)

AF:

0.0260

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.0125

ESP6500AA

AF:

0.00138

AC:

ESP6500EA

AF:

0.0118

AC:

100

ExAC

AF:

0.0119

AC:

1424

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0213

EpiControl

AF:

0.0214

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

MRPS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.9

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.050

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.46

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.81

REVEL

Benign

0.021

Sift

Benign

0.16

Sift4G

Benign

0.062

Polyphen

0.24

Vest4

0.063

MPC

0.30

ClinPred

0.011

GERP RS

1.2

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.044

gMVP

0.34

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over