rs1227035820

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-25592837-C-A
• chr21-25592837-C-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM2 PP2 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 (★). ClinVar reports functional evidence for this variant: "SCV004801526: 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).".

• 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
• Publications: 0 publications found

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]

MRPL39 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004801526: 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).
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.37309 (below the threshold of 3.09). Trascript score misZ: -0.3663 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial disease.
• 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 VariationId is 1525985.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017446.4. 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
	MRPL39	NM_017446.4	MANE Select	c.896G>T	p.Gly299Val	missense	Exon 8 of 10	NP_059142.3
	MRPL39	NM_080794.4		c.896G>T	p.Gly299Val	missense	Exon 8 of 11	NP_542984.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL39	ENST00000352957.9	TSL:1 MANE Select	c.896G>T	p.Gly299Val	missense	Exon 8 of 10	ENSP00000284967.7	Q9NYK5-1
	MRPL39	ENST00000307301.11	TSL:5	c.896G>T	p.Gly299Val	missense	Exon 8 of 11	ENSP00000305682.7	Q9NYK5-2
	MRPL39	ENST00000925346.1		c.914G>T	p.Gly305Val	missense	Exon 8 of 10	ENSP00000595405.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251068 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial disease (2)
1	-	-	Combined oxidative phosphorylation deficiency 59 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.88		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
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs1227035820; hg19: chr21-26965149;