12-93501210-A-G

Position:

• chr12-93501210-A-G

Variant summary

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

The ENST00000549982.6(MRPL42):​c.418A>G​(p.Lys140Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MRPL42 ENST00000549982.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

Genes affected

MRPL42 (HGNC:14493): (mitochondrial ribosomal protein L42) 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 protein identified as belonging to both the 28S and the 39S subunits. Alternative splicing results in multiple transcript variants. Pseudogenes corresponding to this gene are found on chromosomes 4q, 6p, 6q, 7p, and 15q. [provided by RefSeq, May 2011]

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=0.2443093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL42	NM_014050.4	c.418A>G	p.Lys140Glu	missense_variant	6/6	ENST00000549982.6	NP_054769.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL42	ENST00000549982.6	c.418A>G	p.Lys140Glu	missense_variant	6/6	1	NM_014050.4	ENSP00000449884	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449910 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 720924

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jul 17, 2023

The c.418A>G (p.K140E) alteration is located in exon 6 (coding exon 5) of the MRPL42 gene. This alteration results from a A to G substitution at nucleotide position 418, causing the lysine (K) at amino acid position 140 to be replaced by a glutamic acid (E). 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	0.25
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	.;.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	0.92	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.49	P;P;.
Vest4		0.31
MutPred		0.51		Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);.;
MVP		0.30
MPC		0.44
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs1953589843; hg19: chr12-93894986;