NM_032014.3:c.194G>A

Variant names:

• chr7-43868989-C-T
• rs1246698120
• NM_032014.3:c.194G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032014.3(MRPS24):​c.194G>A​(p.Arg65His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MRPS24 NM_032014.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09
• Publications: 1 publications found

Genes affected

MRPS24 (HGNC:14510): (mitochondrial ribosomal protein S24) 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 28S subunit protein. A pseudogene corresponding to this gene is found on chromosome 11. Read-through transcription exists between this gene and the upstream upregulator of cell proliferation (URGCP) gene. [provided by RefSeq, Mar 2011]

URGCP-MRPS24 (HGNC:49188): (URGCP-MRPS24 readthrough) This locus represents naturally occurring read-through transcription between the neighboring URGCP (upregulator of cell proliferation) and MRPS24 (mitochondrial ribosomal protein S24) genes on chromosome 7. The read-through transcript is predicted to encode a protein that shares sequence identity with the upstream gene product but its C-terminal region is distinct due to a frameshift relative to the downstream gene. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032014.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS24	NM_032014.3	MANE Select	c.194G>A	p.Arg65His	missense	Exon 3 of 4	NP_114403.1	Q96EL2
	URGCP-MRPS24	NM_001204871.2		c.330G>A	p.Pro110Pro	synonymous	Exon 6 of 7	NP_001191800.1	S4R325

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPS24	ENST00000317534.6	TSL:1 MANE Select	c.194G>A	p.Arg65His	missense	Exon 3 of 4	ENSP00000318158.5	Q96EL2
	URGCP-MRPS24	ENST00000603700.1	TSL:5	c.330G>A	p.Pro110Pro	synonymous	Exon 6 of 7	ENSP00000473871.1	S4R325
	MRPS24	ENST00000934254.1		c.194G>A	p.Arg65His	missense	Exon 3 of 4	ENSP00000604313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250888 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.27	B
Vest4		0.89
MutPred		0.78		Gain of ubiquitination at K66 (P = 0.0462)
MVP		0.60
MPC		0.31
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.67
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs1246698120; hg19: chr7-43908588;