9-135503655-G-A

Variant names:

• chr9-135503655-G-A
• rs758539748
• NM_016034.5:c.413G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 PP5

The NM_016034.5(MRPS2):​c.413G>A​(p.Arg138His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000883151: PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/29576219).".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MRPS2 NM_016034.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.63
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 36

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000226706 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883151: PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/29576219).
• PP5: Variant 9-135503655-G-A is Pathogenic according to our data. Variant chr9-135503655-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523225.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS2	NM_016034.5	MANE Select	c.413G>A	p.Arg138His	missense	Exon 4 of 4	NP_057118.1	Q9Y399
	MRPS2	NM_001371401.1		c.413G>A	p.Arg138His	missense	Exon 5 of 5	NP_001358330.1	Q9Y399
	MRPS2	NR_051967.3		n.585G>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS2	ENST00000241600.10	TSL:1 MANE Select	c.413G>A	p.Arg138His	missense	Exon 4 of 4	ENSP00000241600.5	Q9Y399
	ENSG00000226706	ENST00000415062.1	TSL:1	n.735C>T		non_coding_transcript_exon	Exon 3 of 3
	MRPS2	ENST00000371785.5	TSL:3	c.413G>A	p.Arg138His	missense	Exon 5 of 5	ENSP00000360850.1	Q9Y399

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000518 AC: 13 AN: 251206 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461562 Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Combined oxidative phosphorylation deficiency 36 (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.46		Loss of MoRF binding (P = 0.0249)
MVP		0.89
MPC		0.94
ClinPred		0.69	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.81
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs758539748; hg19: chr9-138395501;