chr5-69229208-C-T

Position:

chr5-69229208-C-T

Variant summary

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

The NM_033281.6(KGD4):c.295C>T(p.Arg99Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000336 in 1,609,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

KGD4
NM_033281.6 missense, splice_region

Scores

Splicing: ADA: 0.9752

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

KGD4 (HGNC:16631): (alpha-ketoglutarate dehydrogenase subunit 4) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. The mitochondrial ribosome (mitoribosome) consists 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. Pseudogenes corresponding to this gene are found on chromosomes 3p, 4q, 8p, 11q, 12q, and 20p. [provided by RefSeq, Jul 2008]

KGD4 links:

MRPS36 (HGNC:):

MRPS36 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KGD4	NM_033281.6 linkuse as main transcript	c.295C>T	p.Arg99Cys	missense_variant, splice_region_variant	4/4	ENST00000256441.5	NP_150597.1	P82909

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MRPS36	ENST00000256441.5 linkuse as main transcript	c.295C>T	p.Arg99Cys	missense_variant, splice_region_variant	4/4	1	NM_033281.6	ENSP00000256441.4	P82909
MRPS36	ENST00000512880.5 linkuse as main transcript	c.100C>T	p.Arg34Cys	missense_variant, splice_region_variant	4/4	5		ENSP00000423659.1	D6R941
MRPS36	ENST00000602380.1 linkuse as main transcript	c.100C>T	p.Arg34Cys	missense_variant, splice_region_variant	4/4	2		ENSP00000473310.1	D6R941
MRPS36	ENST00000507022.1 linkuse as main transcript	n.275C>T		splice_region_variant, non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000280

AC:

AN:

249682

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000165

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000336

AC:

AN:

1457696

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

725234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000991

Gnomad4 OTH exome

AF:

0.000482

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151804

Hom.:

Cov.:

AF XY:

0.0000675

AC XY:

AN XY:

74118

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.00578

AC:

AN:

3476

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

Mar 06, 2023

The c.295C>T (p.R99C) alteration is located in exon 4 (coding exon 4) of the MRPS36 gene. This alteration results from a C to T substitution at nucleotide position 295, causing the arginine (R) at amino acid position 99 to be replaced by a cysteine (C). 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

Uncertain

0.53

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.014

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.8

D;D;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.021

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.61

MutPred

0.37

Loss of solvent accessibility (P = 0.0352);.;.;

MVP

0.35

MPC

0.30

ClinPred

0.47

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.83

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