NM_022497.5:c.236A>T

Variant names:

• chr3-15059374-T-A
• rs2042717327
• NM_022497.5:c.236A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_022497.5(MRPS25):​c.236A>T​(p.Tyr79Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. Y79C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MRPS25 NM_022497.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• 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]

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 2 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=0.42243478).

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.236A>T	p.Tyr79Phe	missense	Exon 2 of 4	NP_071942.1	P82663-1
	MRPS25	NR_135246.2		n.357A>T		non_coding_transcript_exon	Exon 2 of 5
	MRPS25	NR_135247.2		n.357A>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.236A>T	p.Tyr79Phe	missense	Exon 2 of 4	ENSP00000253686.2	P82663-1
	MRPS25	ENST00000887322.1		c.236A>T	p.Tyr79Phe	missense	Exon 2 of 4	ENSP00000557381.1
	MRPS25	ENST00000449354.7	TSL:2	c.236A>T	p.Tyr79Phe	missense	Exon 2 of 4	ENSP00000390882.2	P82663-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458606 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725774

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109290

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.056	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Benign	0.38	T
Sift4G	Benign	0.42	T
Polyphen		0.085	B
Vest4		0.58
MutPred		0.72		Loss of sheet (P = 0.1158)
MVP		0.28
MPC		0.66
ClinPred		0.93	D
GERP RS		4.9
Varity_R		0.22
gMVP		0.47
Mutation Taster		=30/70	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: rs2042717327; hg19: chr3-15100881;