chr21-25592837-C-A

Variant names:

• chr21-25592837-C-A
• rs1227035820
• NM_017446.4:c.896G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_017446.4(MRPL39):​c.896G>T​(p.Gly299Val) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.14

Genes affected

MRPL39 (HGNC:14027): (mitochondrial ribosomal protein L39) 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. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 21-25592837-C-A is Pathogenic according to our data. Variant chr21-25592837-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1525985.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL39	NM_017446.4	c.896G>T	p.Gly299Val	missense_variant	Exon 8 of 10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.896G>T	p.Gly299Val	missense_variant	Exon 8 of 11		NP_542984.3
MRPL39	XM_006724026.5	c.896G>T	p.Gly299Val	missense_variant	Exon 8 of 10		XP_006724089.1
MRPL39	XM_011529651.3	c.770G>T	p.Gly257Val	missense_variant	Exon 8 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.896G>T	p.Gly299Val	missense_variant	Exon 8 of 10	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.896G>T	p.Gly299Val	missense_variant	Exon 8 of 11	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.866G>T	p.Gly289Val	missense_variant	Exon 8 of 8	5		ENSP00000404426.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Pathogenic:2

Feb 04, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MRPL39 c.896G>T p.(Gly299Val) variant has been identified in a homozygous state in individuals with a phenotype consistent with primary mitochondrial disease. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. Functional studies) conducted in cell lines derived from patient fibroblasts demonstrated that this variant results in decreased expression of MRPL39 proteins which was corrected using lentiviral-mediated expression of wild-type MRPL39 (PMID: 37133451).Based on the available evidence, the c.896G>T p.(Gly299Val) variant is classified as likely pathogenic for primary mitochondrial disease. -

Mar 24, 2022

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Combined oxidative phosphorylation deficiency 59 Pathogenic:1

Dec 04, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.1	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.88		Loss of catalytic residue at V300 (P = 0.1373);Loss of catalytic residue at V300 (P = 0.1373);.;
MVP		0.96
MPC		0.28
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.89

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: rs1227035820; hg19: chr21-26965149;