Genetic Variant NM_014018.3:c.196G>C (chr8-80030053-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014018.3(MRPS28):c.196G>C(p.Val66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MRPS28
NM_014018.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Variant links:

Genes affected

MRPS28 (HGNC:14513): (mitochondrial ribosomal protein S28) 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 that has been called mitochondrial ribosomal protein S35 in the literature. [provided by RefSeq, Jul 2008]

MRPS28 links:

ENSG00000276418 (HGNC:):

ENSG00000276418 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.071891755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPS28	NM_014018.3 link	c.196G>C	p.Val66Leu	missense_variant	Exon 1 of 3	ENST00000276585.9	NP_054737.1	Q9Y2Q9A0A0S2Z563
TPD52-MRPS28	NM_001387778.1 link	c.435+12567G>C		intron_variant	Intron 5 of 6		NP_001374707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPS28	ENST00000276585.9 link	c.196G>C	p.Val66Leu	missense_variant	Exon 1 of 3	1	NM_014018.3	ENSP00000276585.4		Q9Y2Q9
ENSG00000276418	ENST00000522938.5 link	n.555+12567G>C		intron_variant	Intron 5 of 7	2		ENSP00000430858.2		H0YC42

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.0039

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.072

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.83

N;N

REVEL

Benign

0.019

Sift

Benign

0.17

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.022

B;.

Vest4

0.18

MutPred

0.14

Loss of methylation at K65 (P = 0.0469);Loss of methylation at K65 (P = 0.0469);

MVP

0.36

MPC

0.12

ClinPred

0.073

Varity_R

0.17

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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