8-80030065-G-A

Position:

• chr8-80030065-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014018.3(MRPS28):​c.184C>T​(p.Leu62Phe) 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 1,461,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRPS28 NM_014018.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610

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 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=0.24335223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS28	NM_014018.3	c.184C>T	p.Leu62Phe	missense_variant	1/3	ENST00000276585.9	NP_054737.1
TPD52-MRPS28	NM_001387778.1	c.435+12555C>T		intron_variant			NP_001374707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS28	ENST00000276585.9	c.184C>T	p.Leu62Phe	missense_variant	1/3	1	NM_014018.3	ENSP00000276585.4
ENSG00000276418	ENST00000522938.5	n.555+12555C>T		intron_variant		2		ENSP00000430858.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461230 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726856

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 06, 2021

The c.184C>T (p.L62F) alteration is located in exon 1 (coding exon 1) of the MRPS28 gene. This alteration results from a C to T substitution at nucleotide position 184, causing the leucine (L) at amino acid position 62 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.99	N;D
REVEL	Benign	0.14
Sift	Benign	0.14	T;T
Sift4G	Benign	0.29	T;D
Polyphen		0.99	D;.
Vest4		0.41
MutPred		0.20		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);
MVP		0.64
MPC		0.17
ClinPred		0.54	D
GERP RS		-1.4
Varity_R		0.072
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1809615066; hg19: chr8-80942300;