19-5692064-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004793.4(LONP1):​c.2848G>A​(p.Glu950Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E950D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

LONP1
NM_004793.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29
Variant links:
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]
RPL36 (HGNC:13631): (ribosomal protein L36) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10327223).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LONP1NM_004793.4 linkc.2848G>A p.Glu950Lys missense_variant Exon 18 of 18 ENST00000360614.8 NP_004784.2 P36776-1
RPL36NM_033643.3 linkc.*443C>T downstream_gene_variant ENST00000347512.8 NP_378669.1 Q9Y3U8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LONP1ENST00000360614.8 linkc.2848G>A p.Glu950Lys missense_variant Exon 18 of 18 1 NM_004793.4 ENSP00000353826.2 P36776-1
RPL36ENST00000347512.8 linkc.*443C>T downstream_gene_variant 1 NM_033643.3 ENSP00000252543.3 Q9Y3U8

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461544
Hom.:
0
Cov.:
34
AF XY:
0.0000110
AC XY:
8
AN XY:
727062
show subpopulations
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 950 of the LONP1 protein (p.Glu950Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LONP1-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LONP1 protein function with a negative predictive value of 95%. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
14
DANN
Benign
0.94
DEOGEN2
Benign
0.12
T;T;.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.41
N
LIST_S2
Benign
0.83
T;T;T;T;T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.10
T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.6
L;.;.;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.52
N;.;.;N;.
REVEL
Benign
0.065
Sift
Benign
0.36
T;.;.;T;.
Sift4G
Benign
0.68
T;T;T;T;T
Polyphen
0.0020
B;.;.;.;.
Vest4
0.28
MutPred
0.54
Gain of ubiquitination at E950 (P = 0.0101);.;.;.;.;
MVP
0.40
MPC
0.37
ClinPred
0.091
T
GERP RS
0.14
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.097
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-5692075; API