Genetic Variant NM_145729.3:c.157G>T (chr1-156738548-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_145729.3(MRPL24):c.157G>T(p.Asp53Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MRPL24
NM_145729.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.27

Variant links:

Genes affected

MRPL24 (HGNC:14037): (mitochondrial ribosomal protein L24) 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 which is more than twice the size of its E.coli counterpart (EcoL24). Sequence analysis identified two transcript variants that encode the same protein. [provided by RefSeq, Jul 2008]

MRPL24 links:

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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 rank	MANE	Protein	UniProt
MRPL24	NM_145729.3 link	c.157G>T	p.Asp53Tyr	missense_variant	Exon 2 of 6	ENST00000361531.6	NP_663781.1	Q96A35
MRPL24	NM_024540.4 link	c.157G>T	p.Asp53Tyr	missense_variant	Exon 2 of 6		NP_078816.2	Q96A35
MRPL24	XM_011509981.3 link	c.157G>T	p.Asp53Tyr	missense_variant	Exon 2 of 6		XP_011508283.1	Q96A35
MRPL24	XM_011509982.3 link	c.157G>T	p.Asp53Tyr	missense_variant	Exon 2 of 6		XP_011508284.1	Q96A35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL24	ENST00000361531.6 link	c.157G>T	p.Asp53Tyr	missense_variant	Exon 2 of 6	1	NM_145729.3	ENSP00000354525.2		Q96A35

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157G>T (p.D53Y) alteration is located in exon 2 (coding exon 1) of the MRPL24 gene. This alteration results from a G to T substitution at nucleotide position 157, causing the aspartic acid (D) at amino acid position 53 to be replaced by a tyrosine (Y). 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

0.16

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

T;T;T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

.;T;T;T;T

M_CAP

Benign

0.0066

MetaRNN

Uncertain

0.46

T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.4

M;M;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.2

D;D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;.;D

Polyphen

0.96

D;D;.;.;.

Vest4

0.63

MutPred

0.43

Gain of phosphorylation at D53 (P = 0.0699);Gain of phosphorylation at D53 (P = 0.0699);Gain of phosphorylation at D53 (P = 0.0699);Gain of phosphorylation at D53 (P = 0.0699);Gain of phosphorylation at D53 (P = 0.0699);

MVP

0.62

MPC

0.88

ClinPred

0.97

GERP RS

4.5

Varity_R

0.60

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over