9-135501043-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.457

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPS2	NM_016034.5	c.89C>A	p.Thr30Asn	missense_variant	2/4	ENST00000241600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPS2	ENST00000241600.10	c.89C>A	p.Thr30Asn	missense_variant	2/4	1	NM_016034.5	P1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1733 AN: 152072 Hom.: 17 Cov.: 33

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

GnomAD3 exomes AF: 0.0134 AC: 3200 AN: 238800 Hom.: 46 AF XY: 0.0136 AC XY: 1792 AN XY: 131536

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 SAS exome AF: 0.00480

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.: 31 AF XY: 0.0143 AC XY: 10351 AN XY: 725634

Gnomad4 AFR exome AF: 0.00371

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0424

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00551

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0176

GnomAD4 genome AF: 0.0114 AC: 1729 AN: 152188 Hom.: 17 Cov.: 33 AF XY: 0.0106 AC XY: 790 AN XY: 74388

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0137 Hom.: 10

Bravo AF: 0.0125

ESP6500AA AF: 0.00138 AC: 6

ESP6500EA AF: 0.0118 AC: 100

ExAC AF: 0.0119 AC: 1424

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0214

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MRPS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	3.9
Dann	Benign	0.82
DEOGEN2	Benign	0.050	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.025	N
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.81	N;N;N
REVEL	Benign	0.021
Sift	Benign	0.16	T;T;D
Sift4G	Benign	0.062	T;T;D
Polyphen		0.24	B;B;.
Vest4		0.063
MPC		0.30
ClinPred		0.011	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.34

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

Other links and lift over

dbSNP: rs140165953; hg19: chr9-138392889;