Genetic Variant NM_022497.5:c.105C>A (chr3-15065090-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022497.5(MRPS25):c.105C>A(p.Asn35Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,820 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.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MRPS25
NM_022497.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.16

Variant links:

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 links:

ENSG00000289750 (HGNC:):

ENSG00000289750 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS25	NM_022497.5 link	c.105C>A	p.Asn35Lys	missense_variant	Exon 1 of 4	ENST00000253686.7	NP_071942.1	P82663-1
MRPS25	NR_135246.2 link	n.226C>A		non_coding_transcript_exon_variant	Exon 1 of 5
MRPS25	NR_135247.2 link	n.226C>A		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS25	ENST00000253686.7 link	c.105C>A	p.Asn35Lys	missense_variant	Exon 1 of 4	1	NM_022497.5	ENSP00000253686.2		P82663-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722554

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

0.0033

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.8

M;M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-4.4

D;D;D

REVEL

Uncertain

0.30

Sift

Benign

0.068

T;T;T

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MutPred

0.54

Gain of ubiquitination at N35 (P = 0.0289);Gain of ubiquitination at N35 (P = 0.0289);Gain of ubiquitination at N35 (P = 0.0289);

MVP

0.37

MPC

0.57

ClinPred

0.99

GERP RS

3.0

Varity_R

0.58

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over