11-1952179-G-T

Variant names:

• chr11-1952179-G-T
• rs368383014
• NM_021134.4:c.193G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_021134.4(MRPL23):​c.193G>T​(p.Val65Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V65M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 1)
  • Failed GnomAD Quality Control
• Consequence: MRPL23 NM_021134.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

MRPL23 (HGNC:10322): (mitochondrial ribosomal protein L23) 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. The gene is biallelically expressed, despite its location within a region of imprinted genes on chromosome 11. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021134.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL23	NM_021134.4	MANE Select	c.193G>T	p.Val65Leu	missense	Exon 3 of 5	NP_066957.3
	MRPL23	NM_001400176.1		c.193G>T	p.Val65Leu	missense	Exon 3 of 7	NP_001387105.1
	MRPL23	NM_001400179.1		c.193G>T	p.Val65Leu	missense	Exon 3 of 6	NP_001387108.1	A8MYK1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL23	ENST00000397298.8	TSL:1 MANE Select	c.193G>T	p.Val65Leu	missense	Exon 3 of 5	ENSP00000380466.3	Q16540
	MRPL23	ENST00000924183.1		c.193G>T	p.Val65Leu	missense	Exon 3 of 5	ENSP00000594242.1
	MRPL23	ENST00000397297.7	TSL:2	c.193G>T	p.Val65Leu	missense	Exon 3 of 6	ENSP00000380465.3	A8MYK1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 9014 Hom.: 0 Cov.: 1

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 9014 Hom.: 0 Cov.: 1 AF XY: 0.00 AC XY: 0 AN XY: 3788

African (AFR) AF: 0.00 AC: 0 AN: 762

American (AMR) AF: 0.00 AC: 0 AN: 480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 300

East Asian (EAS) AF: 0.00 AC: 0 AN: 136

South Asian (SAS) AF: 0.00 AC: 0 AN: 84

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6604

Other (OTH) AF: 0.00 AC: 0 AN: 108

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.066	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.84		Gain of catalytic residue at V65 (P = 0.0544)
MVP		0.47
MPC		0.67
ClinPred		0.97	D
GERP RS		2.9
Varity_R		0.95
gMVP		0.59
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs368383014; hg19: chr11-1973409;