rs879255249

Positions:

• chr19-5694536-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 16) in uniprot entity LONM_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004793.4
• 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 id is 180660.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-5694536-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LONP1	NM_004793.4	c.2171C>T	p.Ala724Val	missense_variant	15/18	ENST00000360614.8
LONP1	NM_001276479.2	c.1979C>T	p.Ala660Val	missense_variant	16/19
LONP1	NM_001276480.1	c.1583C>T	p.Ala528Val	missense_variant	15/18
LONP1	NR_076392.2	n.1976C>T		non_coding_transcript_exon_variant	16/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LONP1	ENST00000360614.8	c.2171C>T	p.Ala724Val	missense_variant	15/18	1	NM_004793.4	P1

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

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

CODAS syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D;.;.;D;.;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D;.;.;T;.;.
Sift4G	Pathogenic	0.0010	D;D;D;T;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
Varity_R		0.88
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs879255249; hg19: chr19-5694547;