2-105080018-T-G

Variant names:

• chr2-105080018-T-G
• rs202077550
• NM_182640.3:c.445T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_182640.3(MRPS9):​c.445T>G​(p.Tyr149Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000204 in 1,611,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y149C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: MRPS9 NM_182640.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04

Genes affected

MRPS9 (HGNC:14501): (mitochondrial ribosomal protein S9) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS9	NM_182640.3	c.445T>G	p.Tyr149Asp	missense_variant	Exon 5 of 11	ENST00000258455.8	NP_872578.1
MRPS9	XM_011511644.3	c.73T>G	p.Tyr25Asp	missense_variant	Exon 4 of 10		XP_011509946.1
MRPS9	XM_047445533.1	c.445T>G	p.Tyr149Asp	missense_variant	Exon 5 of 7		XP_047301489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS9	ENST00000258455.8	c.445T>G	p.Tyr149Asp	missense_variant	Exon 5 of 11	1	NM_182640.3	ENSP00000258455.3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 250052 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 135176

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.000213 AC: 311 AN: 1459598 Hom.: 0 Cov.: 29 AF XY: 0.000197 AC XY: 143 AN XY: 726170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000548

EpiControl AF: 0.000357

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.445T>G (p.Y149D) alteration is located in exon 5 (coding exon 5) of the MRPS9 gene. This alteration results from a T to G substitution at nucleotide position 445, causing the tyrosine (Y) at amino acid position 149 to be replaced by an aspartic acid (D). 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	0.26
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.011	D
Sift4G	Benign	0.19	T
Polyphen		0.96	D
Vest4		0.62
MVP		0.97
MPC		0.48
ClinPred		0.28	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.51
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202077550; hg19: chr2-105696476;