7-141010512-G-A

Position:

• chr7-141010512-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_053035.3(MRPS33):​c.122C>T​(p.Pro41Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,886 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: 0.0000041 (0 hom.)
• Consequence: MRPS33 NM_053035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.80

Genes affected

MRPS33 (HGNC:16634): (mitochondrial ribosomal protein S33) 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. The 28S subunit of the mammalian mitoribosome may play a crucial and characteristic role in translation initiation. This gene encodes a 28S subunit protein that is one of the more highly conserved mitochondrial ribosomal proteins among mammals, Drosophila and C. elegans. Splice variants that differ in the 5' UTR have been found for this gene; all variants encode the same protein. Pseudogenes corresponding to this gene are found on chromosomes 1q, 4p, 4q, and 20q [provided by RefSeq, Jul 2008]

MRPS33 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS33	NM_053035.3	c.122C>T	p.Pro41Leu	missense_variant	2/3	ENST00000324787.10	NP_444263.1
MRPS33	NM_016071.4	c.122C>T	p.Pro41Leu	missense_variant	2/3		NP_057155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS33	ENST00000324787.10	c.122C>T	p.Pro41Leu	missense_variant	2/3	1	NM_053035.3	ENSP00000320567.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

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

Mar 29, 2023

The c.122C>T (p.P41L) alteration is located in exon 2 (coding exon 1) of the MRPS33 gene. This alteration results from a C to T substitution at nucleotide position 122, causing the proline (P) at amino acid position 41 to be replaced by a leucine (L). 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	0.59
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;T;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;.;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-9.6	D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.90
MutPred		0.63		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);.;
MVP		0.19
MPC		0.49
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.80

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: rs1259576691; hg19: chr7-140710312;