16-369123-A-G

Position:

chr16-369123-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006428.5(MRPL28):c.386T>C(p.Met129Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MRPL28
NM_006428.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.85

Variant links:

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]

MRPL28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11773077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MRPL28	NM_006428.5 linkuse as main transcript	c.386T>C	p.Met129Thr	missense_variant	3/6	ENST00000199706.13	NP_006419.2
MRPL28	XM_005255041.3 linkuse as main transcript	c.386T>C	p.Met129Thr	missense_variant	3/6		XP_005255098.1
MRPL28	XM_011522351.3 linkuse as main transcript	c.386T>C	p.Met129Thr	missense_variant	3/6		XP_011520653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL28	ENST00000199706.13 linkuse as main transcript	c.386T>C	p.Met129Thr	missense_variant	3/6	1	NM_006428.5	ENSP00000199706	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251360

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.386T>C (p.M129T) alteration is located in exon 3 (coding exon 2) of the MRPL28 gene. This alteration results from a T to C substitution at nucleotide position 386, causing the methionine (M) at amino acid position 129 to be replaced by a threonine (T). 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

0.27

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.0066

T;T;T;T;T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.81

.;.;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.12

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M;M;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.27

.;N;N;N;N;N

REVEL

Benign

0.071

Sift

Benign

0.57

.;T;T;T;T;T

Sift4G

Benign

0.57

.;T;T;.;.;.

Polyphen

0.13

B;B;B;B;.;.

Vest4

0.41, 0.41

MutPred

0.39

Loss of catalytic residue at V125 (P = 0.0338);Loss of catalytic residue at V125 (P = 0.0338);Loss of catalytic residue at V125 (P = 0.0338);Loss of catalytic residue at V125 (P = 0.0338);Loss of catalytic residue at V125 (P = 0.0338);Loss of catalytic residue at V125 (P = 0.0338);

MVP

0.16

ClinPred

0.057

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over