3-15052482-C-A

Variant names:

• chr3-15052482-C-A
• rs747489176
• NM_022497.5:c.481G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_022497.5(MRPS25):​c.481G>T​(p.Gly161Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MRPS25 NM_022497.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77
• Publications: 1 publications found

Genes affected

MRPS25 (HGNC:14511): (mitochondrial ribosomal protein S25) 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. A pseudogene corresponding to this gene is found on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

NR2C2 (HGNC:7972): (nuclear receptor subfamily 2 group C member 2) This gene encodes a protein that belongs to the nuclear hormone receptor family. Members of this family act as ligand-activated transcription factors and function in many biological processes such as development, cellular differentiation and homeostasis. The activated receptor/ligand complex is translocated to the nucleus where it binds to hormone response elements of target genes. The protein encoded by this gene plays a role in protecting cells from oxidative stress and damage induced by ionizing radiation. The lack of a similar gene in mouse results in growth retardation, severe spinal curvature, subfertility, premature aging, and prostatic intraepithelial neoplasia (PIN) development. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

ENSG00000289750 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.80938 (below the threshold of 3.09). Trascript score misZ: -0.035476 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial encephalomyopathy, combined oxidative phosphorylation deficiency 50.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022497.5. 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
	MRPS25	NM_022497.5	MANE Select	c.481G>T	p.Gly161Trp	missense	Exon 4 of 4	NP_071942.1	P82663-1
	MRPS25	NR_135246.2		n.691G>T		non_coding_transcript_exon	Exon 4 of 5
	MRPS25	NR_135247.2		n.602G>T		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS25	ENST00000253686.7	TSL:1 MANE Select	c.481G>T	p.Gly161Trp	missense	Exon 4 of 4	ENSP00000253686.2	P82663-1
	MRPS25	ENST00000887322.1		c.469G>T	p.Gly157Trp	missense	Exon 4 of 4	ENSP00000557381.1
	MRPS25	ENST00000939927.1		c.397G>T	p.Gly133Trp	missense	Exon 4 of 4	ENSP00000609986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251422 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.64		Loss of disorder (P = 0.0036)
MVP		0.30
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.91
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs747489176; hg19: chr3-15093989;