16-370043-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006428.5(MRPL28):c.176G>C(p.Arg59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,190 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: MRPL28 NM_006428.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.95

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016733885).
• BP6: Variant 16-370043-C-G is Benign according to our data. Variant chr16-370043-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 254105.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL28	NM_006428.5	c.176G>C	p.Arg59Pro	missense_variant	2/6	ENST00000199706.13
MRPL28	XM_005255041.3	c.176G>C	p.Arg59Pro	missense_variant	2/6
MRPL28	XM_011522351.3	c.176G>C	p.Arg59Pro	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL28	ENST00000199706.13	c.176G>C	p.Arg59Pro	missense_variant	2/6	1	NM_006428.5	P1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152148 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000514 AC: 128 AN: 249238 Hom.: 0 AF XY: 0.000540 AC XY: 73 AN XY: 135246

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000507

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000391 AC: 571 AN: 1460924 Hom.: 0 Cov.: 34 AF XY: 0.000409 AC XY: 297 AN XY: 726770

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152266 Hom.: 0 Cov.: 34 AF XY: 0.000349 AC XY: 26 AN XY: 74438

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000582

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000831

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Oromandibular-limb hypogenesis spectrum Benign:1

Likely benign, no assertion criteria provided

research

CHU Sainte-Justine Research Center, University of Montreal

Aug 12, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Benign	0.91
DEOGEN2	Benign	0.015	T;T;T;T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.017	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.43	T
Polyphen		0.0080	B;B;B;B;.;.
Vest4		0.57
MVP		0.48
ClinPred		0.014	T
GERP RS		3.9
Varity_R		0.80
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149440376; hg19: chr16-420043;