9-135500724-C-G

Variant names:

• chr9-135500724-C-G
• rs770946612
• NM_016034.5:c.14C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016034.5(MRPS2):​c.14C>G​(p.Ser5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000752 in 1,328,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S5L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MRPS2 NM_016034.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719
• Publications: 0 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]

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17985588).

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.14C>G	p.Ser5Trp	missense	Exon 1 of 4	NP_057118.1	Q9Y399
	MRPS2	NM_001371401.1		c.14C>G	p.Ser5Trp	missense	Exon 2 of 5	NP_001358330.1	Q9Y399
	MRPS2	NR_051967.3		n.43C>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS2	ENST00000241600.10	TSL:1 MANE Select	c.14C>G	p.Ser5Trp	missense	Exon 1 of 4	ENSP00000241600.5	Q9Y399
	PIERCE1	ENST00000371791.5	TSL:1	c.-64-809G>C		intron	N/A	ENSP00000360856.1	Q5BN46-2
	MRPS2	ENST00000371785.5	TSL:3	c.14C>G	p.Ser5Trp	missense	Exon 2 of 5	ENSP00000360850.1	Q9Y399

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.52e-7 AC: 1 AN: 1328922 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 652084

African (AFR) AF: 0.00 AC: 0 AN: 27238

American (AMR) AF: 0.00 AC: 0 AN: 26814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21492

East Asian (EAS) AF: 0.00 AC: 0 AN: 32536

South Asian (SAS) AF: 0.00 AC: 0 AN: 69942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4810

European-Non Finnish (NFE) AF: 9.49e-7 AC: 1 AN: 1053770

Other (OTH) AF: 0.00 AC: 0 AN: 55238

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.9
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.72
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.033
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.013	D
Polyphen		0.89	P
Vest4		0.23
MutPred		0.34		Gain of MoRF binding (P = 0.0039)
MVP		0.64
MPC		0.63
ClinPred		0.51	D
GERP RS		-0.025
PromoterAI		0.13	Neutral
Varity_R		0.062
gMVP		0.35
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs770946612; hg19: chr9-138392570;