rs879255249

Variant names:

• chr19-5694536-G-A
• rs879255249
• NM_004793.4:c.2171C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004793.4(LONP1):​c.2171C>T​(p.Ala724Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LONP1 NM_004793.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.07
• Publications: 3 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• pyruvate dehydrogenase E1-alpha deficiency

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

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Ambry Genetics
• 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
• PP5: Variant 19-5694536-G-A is Pathogenic according to our data. Variant chr19-5694536-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 180660.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	NM_004793.4	MANE Select	c.2171C>T	p.Ala724Val	missense	Exon 15 of 18	NP_004784.2
	LONP1	NM_001276479.2		c.1979C>T	p.Ala660Val	missense	Exon 16 of 19	NP_001263408.1	P36776-2
	LONP1	NM_001276480.1		c.1583C>T	p.Ala528Val	missense	Exon 15 of 18	NP_001263409.1	P36776-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	ENST00000360614.8	TSL:1 MANE Select	c.2171C>T	p.Ala724Val	missense	Exon 15 of 18	ENSP00000353826.2	P36776-1
	LONP1	ENST00000590729.5	TSL:1	c.1781C>T	p.Ala594Val	missense	Exon 15 of 18	ENSP00000465139.1	K7EJE8
	LONP1	ENST00000958482.1		c.2171C>T	p.Ala724Val	missense	Exon 15 of 19	ENSP00000628541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460634 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726618

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	CODAS syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.34	B
Vest4		0.92
MutPred		0.54		Gain of methylation at K722 (P = 0.0769)
MVP		0.30
MPC		0.52
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		-0.095	Neutral
Varity_R		0.88
gMVP		0.85
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs879255249; hg19: chr19-5694547;