1-156738344-G-A

Variant names:

• chr1-156738344-G-A
• rs1022563019
• NM_145729.3:c.278C>T

Variant summary

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

The NM_145729.3(MRPL24):​c.278C>T​(p.Thr93Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000131 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: MRPL24 NM_145729.3 missense, splice_region
• Scores: Splicing: ADA: 0.1153
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47

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]

ACMG classification

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	c.278C>T	p.Thr93Ile	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000361531.6	NP_663781.1
MRPL24	NM_024540.4	c.278C>T	p.Thr93Ile	missense_variant, splice_region_variant	Exon 3 of 6		NP_078816.2
MRPL24	XM_011509981.3	c.278C>T	p.Thr93Ile	missense_variant, splice_region_variant	Exon 3 of 6		XP_011508283.1
MRPL24	XM_011509982.3	c.278C>T	p.Thr93Ile	missense_variant, splice_region_variant	Exon 3 of 6		XP_011508284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL24	ENST00000361531.6	c.278C>T	p.Thr93Ile	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_145729.3	ENSP00000354525.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

Gnomad4 AFR AF: 0.0000483

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.278C>T (p.T93I) alteration is located in exon 3 (coding exon 2) of the MRPL24 gene. This alteration results from a C to T substitution at nucleotide position 278, causing the threonine (T) at amino acid position 93 to be replaced by an isoleucine (I). 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	0.15
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T;T;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.0024	T
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.47	T;T;T;T
Sift4G	Benign	0.43	T;T;T;.
Polyphen		0.48	P;P;.;.
Vest4		0.63
MutPred		0.64		Loss of catalytic residue at T93 (P = 0.0444);Loss of catalytic residue at T93 (P = 0.0444);Loss of catalytic residue at T93 (P = 0.0444);Loss of catalytic residue at T93 (P = 0.0444);
MVP		0.69
MPC		0.59
ClinPred		0.91	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.23
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

LitVar

Other links and lift over

dbSNP: rs1022563019; hg19: chr1-156708136; COSMIC: COSV100625666; COSMIC: COSV100625666;