16-369939-T-G

Variant summary

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

The NM_006428.5(MRPL28):c.280A>C(p.Asn94His) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: MRPL28 NM_006428.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.259

Genes affected

MRPL28 (HGNC:14484): (mitochondrial ribosomal protein L28) 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 39S subunit protein, a part of which was originally isolated by its ability to recognize tyrosinase in an HLA-A24-restricted fashion. [provided by RefSeq, Jul 2008]

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=0.21072978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL28	NM_006428.5	c.280A>C	p.Asn94His	missense_variant	2/6	ENST00000199706.13
MRPL28	XM_005255041.3	c.280A>C	p.Asn94His	missense_variant	2/6
MRPL28	XM_011522351.3	c.280A>C	p.Asn94His	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL28	ENST00000199706.13	c.280A>C	p.Asn94His	missense_variant	2/6	1	NM_006428.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

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

Jan 23, 2023

The c.280A>C (p.N94H) alteration is located in exon 2 (coding exon 1) of the MRPL28 gene. This alteration results from a A to C substitution at nucleotide position 280, causing the asparagine (N) at amino acid position 94 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	13
Dann	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;T;T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.31	T
Polyphen		0.98	D;D;D;D;.;.
Vest4		0.25, 0.25
MutPred		0.41		Gain of disorder (P = 0.0962);Gain of disorder (P = 0.0962);Gain of disorder (P = 0.0962);Gain of disorder (P = 0.0962);Gain of disorder (P = 0.0962);Gain of disorder (P = 0.0962);
MVP		0.47
ClinPred		0.63	D
GERP RS		-1.8
Varity_R		0.092
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr16-419939;