9-135500741-A-G

Position:

• chr9-135500741-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016034.5(MRPS2):​c.31A>G​(p.Ile11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,460 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MRPS2 NM_016034.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0990

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]

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]

ACMG classification

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=0.038541853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS2	NM_016034.5	c.31A>G	p.Ile11Val	missense_variant	1/4	ENST00000241600.10	NP_057118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS2	ENST00000241600.10	c.31A>G	p.Ile11Val	missense_variant	1/4	1	NM_016034.5	ENSP00000241600.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1331460 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 653046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000181

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.31A>G (p.I11V) alteration is located in exon 1 (coding exon 1) of the MRPS2 gene. This alteration results from a A to G substitution at nucleotide position 31, causing the isoleucine (I) at amino acid position 11 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.2
DANN	Benign	0.51
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.33	.;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.050	N;N
REVEL	Benign	0.0080
Sift	Benign	0.22	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0010	B;B
Vest4		0.11
MutPred		0.28		Gain of methylation at R10 (P = 0.0404);Gain of methylation at R10 (P = 0.0404);
MVP		0.22
MPC		0.19
ClinPred		0.11	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1468996391; hg19: chr9-138392587;