rs139747261

Variant names:

• chr3-15059458-T-A
• rs139747261
• NM_022497.5:c.152A>T

Your query was ambiguous. Multiple possible variants found:

• chr3-15059458-T-A
• chr3-15059458-T-C
• chr3-15059458-T-G

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.152A>T​(p.Asn51Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. N51S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRPS25 NM_022497.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• 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]

MRPS25 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• mitochondrial encephalomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• combined oxidative phosphorylation deficiency 50

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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, 0.794

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.152A>T	p.Asn51Ile	missense	Exon 2 of 4	NP_071942.1	P82663-1
	MRPS25	NR_135246.2		n.273A>T		non_coding_transcript_exon	Exon 2 of 5
	MRPS25	NR_135247.2		n.273A>T		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS25	ENST00000253686.7	TSL:1 MANE Select	c.152A>T	p.Asn51Ile	missense	Exon 2 of 4	ENSP00000253686.2	P82663-1
	MRPS25	ENST00000887322.1		c.152A>T	p.Asn51Ile	missense	Exon 2 of 4	ENSP00000557381.1
	MRPS25	ENST00000449354.7	TSL:2	c.152A>T	p.Asn51Ile	missense	Exon 2 of 4	ENSP00000390882.2	P82663-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250198 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460450 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726552

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110974

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000165 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.92	P
Vest4		0.86
MutPred		0.59		Loss of catalytic residue at N51 (P = 0.0013)
MVP		0.18
MPC		1.1
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.79
Mutation Taster		=23/77	disease causing

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

dbSNP: rs139747261; hg19: chr3-15100965;