8-80030053-C-T

Position:

• chr8-80030053-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014018.3(MRPS28):​c.196G>A​(p.Val66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,613,476 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MRPS28 NM_014018.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00

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]

ENSG00000276418 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004841566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS28	NM_014018.3	c.196G>A	p.Val66Met	missense_variant	1/3	ENST00000276585.9	NP_054737.1
TPD52-MRPS28	NM_001387778.1	c.435+12567G>A		intron_variant			NP_001374707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS28	ENST00000276585.9	c.196G>A	p.Val66Met	missense_variant	1/3	1	NM_014018.3	ENSP00000276585.4
ENSG00000276418	ENST00000522938.5	n.555+12567G>A		intron_variant		2		ENSP00000430858.2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000505 AC: 126 AN: 249524 Hom.: 0 AF XY: 0.000474 AC XY: 64 AN XY: 134970

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.00131

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000290 AC: 424 AN: 1461232 Hom.: 0 Cov.: 31 AF XY: 0.000310 AC XY: 225 AN XY: 726874

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74380

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000686 Hom.: 0

Bravo AF: 0.000442

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.196G>A (p.V66M) alteration is located in exon 1 (coding exon 1) of the MRPS28 gene. This alteration results from a G to A substitution at nucleotide position 196, causing the valine (V) at amino acid position 66 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0026	T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.024
Sift	Benign	0.060	T;D
Sift4G	Benign	0.10	T;D
Polyphen		0.46	P;.
Vest4		0.23
MVP		0.40
MPC		0.12
ClinPred		0.019	T
Varity_R		0.14
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200130139; hg19: chr8-80942288; COSMIC: COSV52563501; COSMIC: COSV52563501;