15-88464742-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022163.4(MRPL46):c.550C>T(p.Leu184Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,860 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: 0.0000021 (0 hom.)
• Consequence: MRPL46 NM_022163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.23

Genes affected

MRPL46 (HGNC:1192): (mitochondrial ribosomal protein L46) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL46	NM_022163.4	c.550C>T	p.Leu184Phe	missense_variant	3/4	ENST00000312475.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL46	ENST00000312475.5	c.550C>T	p.Leu184Phe	missense_variant	3/4	1	NM_022163.4	P1
MRPL46	ENST00000558660.1	n.296C>T		non_coding_transcript_exon_variant	2/2	2
MRPL46	ENST00000559538.1	c.73C>T	p.Leu25Phe	missense_variant, NMD_transcript_variant	1/3	3
MRPL46	ENST00000560703.1	c.*102C>T		3_prime_UTR_variant, NMD_transcript_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.550C>T (p.L184F) alteration is located in exon 3 (coding exon 3) of the MRPL46 gene. This alteration results from a C to T substitution at nucleotide position 550, causing the leucine (L) at amino acid position 184 to be replaced by a phenylalanine (F). 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	0.54
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.043	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.65		Loss of helix (P = 0.1299);
MVP		0.85
MPC		0.22
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-89007973; COSMIC: COSV56900617; COSMIC: COSV56900617;