rs1209423257

Variant names:

• chr21-25598338-C-T
• rs1209423257
• NM_017446.4:c.589-924G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_017446.4(MRPL39):​c.589-924G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 151,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: 𝑓 0.000053 (0 hom., cov: 31)
• Consequence: MRPL39 NM_017446.4 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -0.136

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-25598338-C-T is Pathogenic according to our data. Variant chr21-25598338-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1676674.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.589-924G>A		intron_variant	Intron 5 of 9	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.589-924G>A		intron_variant	Intron 5 of 10		NP_542984.3
MRPL39	XM_006724026.5	c.589-924G>A		intron_variant	Intron 5 of 9		XP_006724089.1
MRPL39	XM_011529651.3	c.463-924G>A		intron_variant	Intron 5 of 9		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.589-924G>A		intron_variant	Intron 5 of 9	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.589-924G>A		intron_variant	Intron 5 of 10	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.559-924G>A		intron_variant	Intron 5 of 7	5		ENSP00000404426.1

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 8 AN: 151500 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

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: 0.0000883

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000528 AC: 8 AN: 151500 Hom.: 0 Cov.: 31 AF XY: 0.0000406 AC XY: 3 AN XY: 73922

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Pathogenic:1

Apr 03, 2022

Mitochondrial Research Group, Murdoch Children's Research Institute

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Mitochondrial disease Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with lethal infantile mitochondrial disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0217 - Non-coding variant with predicted effect. RNASeq on patient fibroblasts showed this variant causes mis-splicing resulting a premature termination codon p.(Gln197Argfs*9), which is predicted to lead to nonsense-mediated decay (NMD). RNASeq and immunoblotting showed markedly reduced MRPL39 expression consistent with NMD (PMID: 37133451). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 8 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to bi-allelic loss of function variants (gnomAD). (SP) 0704 - Other NMD-predicted variants comparable to the one identified in this case have limited previous evidence for pathogenicity. Another NMD-predicted variant, p.(Ser176Leufs*8), was reported in a patient with mitochondrial disease in trans with this variant (c.589-924G>A; PMID: 37133451). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. Two patients with lethal infantile mitochondrial disease were found to harbour this variant (PMID: 37133451). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Western blots on patient fibroblasts showed destabilisation of mitoribosome and defective translation of the OXPHOS complexes (PMID: 37133451). (SP) 1205 - This variant has been shown to be maternally inherited. Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Combined oxidative phosphorylation deficiency 59 Pathogenic:1

Mar 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	16
DANN	Benign	0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1209423257; hg19: chr21-26970650;