NM_017446.4:c.436_438delTGTinsAGC

Variant names:

• chr21-25601450-ACA-GCT
• NM_017446.4:c.436_438delTGTinsAGC
• MRPL39 p.Cys146Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_017446.4(MRPL39):​c.436_438delTGTinsAGC​(p.Cys146Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92
• 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.

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.436_438delTGTinsAGC	p.Cys146Ser	missense	N/A	NP_059142.3
	MRPL39	NM_080794.4		c.436_438delTGTinsAGC	p.Cys146Ser	missense	N/A	NP_542984.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL39	ENST00000352957.9	TSL:1 MANE Select	c.436_438delTGTinsAGC	p.Cys146Ser	missense	N/A	ENSP00000284967.7	Q9NYK5-1
	MRPL39	ENST00000307301.11	TSL:5	c.436_438delTGTinsAGC	p.Cys146Ser	missense	N/A	ENSP00000305682.7	Q9NYK5-2
	MRPL39	ENST00000925346.1		c.454_456delTGTinsAGC	p.Cys152Ser	missense	N/A	ENSP00000595405.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-26973762;