15-88465691-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022163.4(MRPL46):c.311A>G(p.Asp104Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPL46 NM_022163.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.120681226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL46	NM_022163.4	c.311A>G	p.Asp104Gly	missense_variant	2/4	ENST00000312475.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL46	ENST00000312475.5	c.311A>G	p.Asp104Gly	missense_variant	2/4	1	NM_022163.4	P1
MRPL46	ENST00000558531.1	c.311A>G	p.Asp104Gly	missense_variant	2/2	2
MRPL46	ENST00000558660.1	n.57A>G		non_coding_transcript_exon_variant	1/2	2
MRPL46	ENST00000560703.1	c.229-815A>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Dec 07, 2021

The c.311A>G (p.D104G) alteration is located in exon 2 (coding exon 2) of the MRPL46 gene. This alteration results from a A to G substitution at nucleotide position 311, causing the aspartic acid (D) at amino acid position 104 to be replaced by a glycine (G). 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	0.088
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	19
Dann	Benign	0.88
DEOGEN2	Benign	0.0042	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.98	N;.
REVEL	Benign	0.064
Sift	Uncertain	0.024	D;.
Sift4G	Benign	0.46	T;T
Polyphen		0.14	B;.
Vest4		0.12
MutPred		0.26		Loss of stability (P = 0.0373);Loss of stability (P = 0.0373);
MVP		0.43
MPC		0.035
ClinPred		0.53	D
GERP RS		4.9
Varity_R		0.29
gMVP		0.48

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: chr15-89008922;