19-5711919-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004793.4(LONP1):c.722G>A(p.Arg241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0801 in 1,613,426 control chromosomes in the GnomAD database, including 6,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R241R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.057 ( 361 hom., cov: 32)

Exomes 𝑓: 0.083 ( 5819 hom. )

Consequence

LONP1
NM_004793.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.02

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

CODAS syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
congenital diaphragmatic hernia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, G2P
mitochondrial encephalomyopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LONP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002746433).

BP6

Variant 19-5711919-C-T is Benign according to our data. Variant chr19-5711919-C-T is described in ClinVar as [Benign]. Clinvar id is 676146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LONP1	NM_004793.4 link	c.722G>A	p.Arg241Gln	missense_variant	Exon 4 of 18	ENST00000360614.8	NP_004784.2	P36776-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LONP1	ENST00000360614.8 link	c.722G>A	p.Arg241Gln	missense_variant	Exon 4 of 18	1	NM_004793.4	ENSP00000353826.2		P36776-1

Frequencies

GnomAD3 genomes

AF:

0.0568

AC:

8637

AN:

152168

Hom.:

361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.0440

Gnomad AMR

AF:

0.0357

Gnomad ASJ

AF:

0.0277

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00993

Gnomad FIN

AF:

0.0817

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0920

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0563

AC:

14109

AN:

250662

AF XY:

0.0561

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0793

Gnomad NFE exome

AF:

0.0907

Gnomad OTH exome

AF:

0.0559

GnomAD4 exome

AF:

0.0825

AC:

120604

AN:

1461140

Hom.:

5819

Cov.:

AF XY:

0.0801

AC XY:

58234

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.0121

AC:

406

AN:

33478

American (AMR)

AF:

0.0249

AC:

1115

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0274

AC:

717

AN:

26124

East Asian (EAS)

AF:

0.000277

AC:

AN:

39694

South Asian (SAS)

AF:

0.0134

AC:

1159

AN:

86258

European-Finnish (FIN)

AF:

0.0805

AC:

4249

AN:

52770

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0977

AC:

108681

AN:

1111946

Other (OTH)

AF:

0.0697

AC:

4211

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

6264

12527

18791

25054

31318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0567

AC:

8634

AN:

152286

Hom.:

361

Cov.:

AF XY:

0.0550

AC XY:

4093

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0165

AC:

687

AN:

41576

American (AMR)

AF:

0.0357

AC:

546

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.00993

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0817

AC:

868

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0920

AC:

6255

AN:

68018

Other (OTH)

AF:

0.0440

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

432

864

1296

1728

2160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0741

Hom.:

1544

Bravo

AF:

0.0519

TwinsUK

AF:

0.0949

AC:

352

ALSPAC

AF:

0.0978

AC:

377

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.0916

AC:

788

ExAC

AF:

0.0590

AC:

7158

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0794

EpiControl

AF:

0.0734

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T;.;.;T

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;D;D;D;D

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.;.;.

PhyloP100

3.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.4

N;.;.;N;.

REVEL

Benign

0.071

Sift

Benign

0.25

T;.;.;T;.

Sift4G

Benign

0.26

T;T;T;T;T

Polyphen

0.063

B;.;.;.;.

Vest4

0.099

MPC

0.52

ClinPred

0.012

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.037

gMVP

0.43

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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19-5711919-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over