chr19-5694889-G-A

Position:

chr19-5694889-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 8.94

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]

LONP1 links:

LONP1 (HGNC:):

LONP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

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: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr19-5694889-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LONP1	NM_004793.4 linkuse as main transcript	c.2026C>T	p.Pro676Ser	missense_variant	14/18	ENST00000360614.8	NP_004784.2	P36776-1
LONP1	NM_001276479.2 linkuse as main transcript	c.1834C>T	p.Pro612Ser	missense_variant	15/19		NP_001263408.1	P36776-2
LONP1	NM_001276480.1 linkuse as main transcript	c.1438C>T	p.Pro480Ser	missense_variant	14/18		NP_001263409.1	P36776-3
LONP1	NR_076392.2 linkuse as main transcript	n.1831C>T		non_coding_transcript_exon_variant	15/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONP1	ENST00000360614.8 linkuse as main transcript	c.2026C>T	p.Pro676Ser	missense_variant	14/18	1	NM_004793.4	ENSP00000353826.2		P36776-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248810

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135094

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000692

AC:

AN:

1445332

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715262

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000909

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

LONP1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2024

The LONP1 c.2026C>T variant is predicted to result in the amino acid substitution p.Pro676Ser. This variant has been reported in the homozygous state in an individual with CODAS syndrome (Strauss et al. 2015. PubMed ID: 25574826). A functional study in this same publication found that the p.Pro676Ser substitution causes decreased peptidase activity of the encoded protein (Strauss et al. 2015. PubMed ID: 25574826). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

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

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;T;.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.1

M;.;.;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.3

D;.;.;D;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

0.97

D;.;.;.;.

Vest4

0.79

MutPred

0.57

Gain of phosphorylation at P676 (P = 0.1565);.;.;.;.;

MVP

0.52

MPC

0.95

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over