chr19-5692052-C-A

Variant summary

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

The NM_004793.4(LONP1):​c.2860G>T​(p.Ala954Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Synonymous variant affecting the same amino acid position (i.e. A954A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

LONP1
NM_004793.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32
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]

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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=0.085069686).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LONP1NM_004793.4 linkuse as main transcriptc.2860G>T p.Ala954Ser missense_variant 18/18 ENST00000360614.8
LONP1NM_001276479.2 linkuse as main transcriptc.2668G>T p.Ala890Ser missense_variant 19/19
LONP1NM_001276480.1 linkuse as main transcriptc.2272G>T p.Ala758Ser missense_variant 18/18
LONP1NR_076392.2 linkuse as main transcriptn.2665G>T non_coding_transcript_exon_variant 19/19

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LONP1ENST00000360614.8 linkuse as main transcriptc.2860G>T p.Ala954Ser missense_variant 18/181 NM_004793.4 P1P36776-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 26, 2022Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. This variant has not been reported in the literature in individuals affected with LONP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 954 of the LONP1 protein (p.Ala954Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
18
DANN
Benign
0.93
DEOGEN2
Benign
0.13
T;T;.;.;T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.50
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.085
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.81
L;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.37
N;.;.;N;.
REVEL
Benign
0.046
Sift
Benign
0.065
T;.;.;T;.
Sift4G
Benign
0.25
T;T;T;T;T
Polyphen
0.016
B;.;.;.;.
Vest4
0.15
MutPred
0.28
Gain of glycosylation at A954 (P = 0.0082);.;.;.;.;
MVP
0.26
MPC
0.32
ClinPred
0.11
T
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2054833252; hg19: chr19-5692063; API