NM_004793.4:c.730_732dupAAG

Variant names:

• chr19-5711908-C-CCTT
• rs560898148
• NM_004793.4:c.730_732dupAAG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_004793.4(LONP1):​c.730_732dupAAG​(p.Lys244dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K244K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LONP1 NM_004793.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 0 publications found

Genes affected

LONP1 (HGNC:9479): (lon peptidase 1, mitochondrial) This gene encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. Decreased expression of this gene has been noted in a patient with hereditary spastic paraplegia (PMID:18378094). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

LONP1 Gene-Disease associations (from GenCC):

• CODAS syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• pyruvate dehydrogenase E1-alpha deficiency

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• congenital diaphragmatic hernia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, G2P
• mitochondrial encephalomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004793.4. Strenght limited to Supporting due to length of the change: 1aa.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004793.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	NM_004793.4	MANE Select	c.730_732dupAAG	p.Lys244dup	conservative_inframe_insertion	Exon 4 of 18	NP_004784.2
	LONP1	NM_001276479.2		c.538_540dupAAG	p.Lys180dup	conservative_inframe_insertion	Exon 5 of 19	NP_001263408.1
	LONP1	NM_001276480.1		c.142_144dupAAG	p.Lys48dup	conservative_inframe_insertion	Exon 4 of 18	NP_001263409.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	ENST00000360614.8	TSL:1 MANE Select	c.730_732dupAAG	p.Lys244dup	conservative_inframe_insertion	Exon 4 of 18	ENSP00000353826.2
	LONP1	ENST00000590729.5	TSL:1	c.388_390dupAAG	p.Lys130dup	conservative_inframe_insertion	Exon 4 of 18	ENSP00000465139.1
	LONP1	ENST00000593119.5	TSL:2	c.538_540dupAAG	p.Lys180dup	conservative_inframe_insertion	Exon 5 of 19	ENSP00000468541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

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

Other links and lift over

dbSNP: rs560898148; hg19: chr19-5711919;