rs879255247
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_004793.4(LONP1):c.2026C>T(p.Pro676Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,445,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
LONP1
NM_004793.4 missense
NM_004793.4 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 8.94
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_004793.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
?
Variant 19-5694889-G-A is Pathogenic according to our data. Variant chr19-5694889-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180658.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr19-5694889-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LONP1 | NM_004793.4 | c.2026C>T | p.Pro676Ser | missense_variant | 14/18 | ENST00000360614.8 | |
LONP1 | NM_001276479.2 | c.1834C>T | p.Pro612Ser | missense_variant | 15/19 | ||
LONP1 | NM_001276480.1 | c.1438C>T | p.Pro480Ser | missense_variant | 14/18 | ||
LONP1 | NR_076392.2 | n.1831C>T | non_coding_transcript_exon_variant | 15/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LONP1 | ENST00000360614.8 | c.2026C>T | p.Pro676Ser | missense_variant | 14/18 | 1 | NM_004793.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248810Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135094
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GnomAD4 exome AF: 0.00000692 AC: 10AN: 1445332Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3AN XY: 715262
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
CODAS syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 08, 2015 | - - |
Neurodevelopmental disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jun 01, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 676 of the LONP1 protein (p.Pro676Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with CODAS syndrome (PMID: 25574826). ClinVar contains an entry for this variant (Variation ID: 180658). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LONP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LONP1 function (PMID: 25574826). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;T;.;.;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MutPred
Gain of phosphorylation at P676 (P = 0.1565);.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at