21-25599860-GA-G

Variant summary

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

The NM_017446.4(MRPL39):c.526del(p.Ser176LeufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: MRPL39 NM_017446.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.971

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 21-25599860-GA-G is Pathogenic according to our data. Variant chr21-25599860-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1676673.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRPL39	NM_017446.4	c.526del	p.Ser176LeufsTer8	frameshift_variant	5/10	ENST00000352957.9
MRPL39	NM_080794.4	c.526del	p.Ser176LeufsTer8	frameshift_variant	5/11
MRPL39	XM_006724026.5	c.526del	p.Ser176LeufsTer8	frameshift_variant	5/10
MRPL39	XM_011529651.3	c.400del	p.Ser134LeufsTer8	frameshift_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRPL39	ENST00000352957.9	c.526del	p.Ser176LeufsTer8	frameshift_variant	5/10	1	NM_017446.4	P1
MRPL39	ENST00000307301.11	c.526del	p.Ser176LeufsTer8	frameshift_variant	5/11	5
MRPL39	ENST00000419219.1	c.521-25del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000235

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000997 AC: 25 AN: 250694 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135554

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000277 AC: 405 AN: 1460916 Hom.: 0 Cov.: 30 AF XY: 0.000268 AC XY: 195 AN XY: 726812

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000355

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

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: 0.000235

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000181

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a suggested 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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 30 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) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 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 the mitoribosome and defective translation of the OXPHOS complexes. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	research	Mitochondrial Research Group, Murdoch Children's Research Institute	Apr 03, 2022	- -

Combined oxidative phosphorylation deficiency 59 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs746607851; hg19: chr21-26972172;