11-68891365-A-C

Position:

• chr11-68891365-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181514.2(MRPL21):​c.584T>G​(p.Ile195Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRPL21 NM_181514.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13

Genes affected

MRPL21 (HGNC:14479): (mitochondrial ribosomal protein L21) 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. Multiple transcript variants encoding different isoforms were identified through sequence analysis although some may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL21	NM_181514.2	c.584T>G	p.Ile195Arg	missense_variant	7/7	ENST00000362034.7	NP_852615.1
MRPL21	NM_181515.2	c.329T>G	p.Ile110Arg	missense_variant	7/7		NP_852616.1
MRPL21	XM_005273823.5	c.*1235T>G		3_prime_UTR_variant	6/6		XP_005273880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL21	ENST00000362034.7	c.584T>G	p.Ile195Arg	missense_variant	7/7	1	NM_181514.2	ENSP00000354580.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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 17, 2023

The c.584T>G (p.I195R) alteration is located in exon 7 (coding exon 7) of the MRPL21 gene. This alteration results from a T to G substitution at nucleotide position 584, causing the isoleucine (I) at amino acid position 195 to be replaced by an arginine (R). 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	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.1	.;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.85		.;Gain of disorder (P = 0.0172);
MVP		0.49
MPC		0.91
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.95
gMVP		0.90

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: rs971909311; hg19: chr11-68658833;