2-74472436-G-C

Position:

• chr2-74472436-G-C

Variant summary

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

The NM_053050.5(MRPL53):​c.127C>G​(p.Arg43Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,596 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: 6.8e-7 (0 hom.)
• Consequence: MRPL53 NM_053050.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

Genes affected

MRPL53 (HGNC:16684): (mitochondrial ribosomal protein L53) 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. A pseudogene corresponding to this gene is found on chromosome 1p. [provided by RefSeq, Jul 2008]

(HGNC:):

CCDC142 (HGNC:25889): (coiled-coil domain containing 142)

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, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL53	NM_053050.5	c.127C>G	p.Arg43Gly	missense_variant	2/3	ENST00000258105.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL53	ENST00000258105.8	c.127C>G	p.Arg43Gly	missense_variant	2/3	1	NM_053050.5	P1
	ENST00000656025.1	n.453G>C		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461596 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727064

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: 8.99e-7

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

Nov 29, 2021

The c.127C>G (p.R43G) alteration is located in exon 2 (coding exon 2) of the MRPL53 gene. This alteration results from a C to G substitution at nucleotide position 127, causing the arginine (R) at amino acid position 43 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	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.53		Gain of loop (P = 0.069);
MVP		0.57
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.75
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs780721569; hg19: chr2-74699563;