chr8-79919003-T-C

Position:

• chr8-79919003-T-C

Variant summary

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

The NM_014018.3(MRPS28):​c.541A>G​(p.Lys181Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPS28 NM_014018.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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=0.07388291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS28	NM_014018.3	c.541A>G	p.Lys181Glu	missense_variant	3/3	ENST00000276585.9	NP_054737.1
TPD52-MRPS28	NM_001387778.1	c.763A>G	p.Lys255Glu	missense_variant	7/7		NP_001374707.1
LOC124901966	XR_007060976.1	n.625-7331T>C		intron_variant
LOC124901966	XR_007060977.1	n.896-10374T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS28	ENST00000276585.9	c.541A>G	p.Lys181Glu	missense_variant	3/3	1	NM_014018.3	ENSP00000276585.4
ENSG00000276418	ENST00000522938.5	n.*225A>G		non_coding_transcript_exon_variant	8/8	2		ENSP00000430858.2
ENSG00000276418	ENST00000522938.5	n.*225A>G		3_prime_UTR_variant	8/8	2		ENSP00000430858.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1409634 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 699494

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Sep 06, 2022

The c.541A>G (p.K181E) alteration is located in exon 3 (coding exon 3) of the MRPS28 gene. This alteration results from a A to G substitution at nucleotide position 541, causing the lysine (K) at amino acid position 181 to be replaced by a glutamic acid (E). 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	0.098
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.016	T;.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.074	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.046
Sift	Uncertain	0.010	D;.;D
Sift4G	Uncertain	0.012	D;D;.
Polyphen		0.0050	B;.;.
Vest4		0.18
MutPred		0.11		Loss of ubiquitination at K181 (P = 0.0023);.;.;
MVP		0.33
MPC		0.31
ClinPred		0.13	T
GERP RS		0.72
Varity_R		0.053
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-80831238;