3-15052506-C-A

Variant names:

• chr3-15052506-C-A
• NM_022497.5:c.457G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_022497.5(MRPS25):​c.457G>T​(p.Val153Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPS25 NM_022497.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18
• Publications: 0 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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.108460784).

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.457G>T	p.Val153Leu	missense	Exon 4 of 4	NP_071942.1	P82663-1
	MRPS25	NR_135246.2		n.667G>T		non_coding_transcript_exon	Exon 4 of 5
	MRPS25	NR_135247.2		n.578G>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.457G>T	p.Val153Leu	missense	Exon 4 of 4	ENSP00000253686.2	P82663-1
	MRPS25	ENST00000887322.1		c.445G>T	p.Val149Leu	missense	Exon 4 of 4	ENSP00000557381.1
	MRPS25	ENST00000939927.1		c.373G>T	p.Val125Leu	missense	Exon 4 of 4	ENSP00000609986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Benign	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Sift4G	Uncertain	0.039	D
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.27		Gain of glycosylation at P154 (P = 0.0932)
MVP		0.20
MPC		0.34
ClinPred		0.70	D
GERP RS		4.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.089
gMVP		0.60
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr3-15094013;