rs139554429

Positions:

chr19-5705830-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004793.4(LONP1):c.1309G>A(p.Val437Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,614,214 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 24 hom. )

Consequence

LONP1
NM_004793.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009248465).

BP6

Variant 19-5705830-C-T is Benign according to our data. Variant chr19-5705830-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 599431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00311 (474/152382) while in subpopulation NFE AF= 0.00448 (305/68040). AF 95% confidence interval is 0.00407. There are 3 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LONP1	NM_004793.4 linkuse as main transcript	c.1309G>A	p.Val437Ile	missense_variant	8/18	ENST00000360614.8	NP_004784.2	P36776-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONP1	ENST00000360614.8 linkuse as main transcript	c.1309G>A	p.Val437Ile	missense_variant	8/18	1	NM_004793.4	ENSP00000353826.2		P36776-1

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

474

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000699

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00809

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00448

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00307

AC:

773

AN:

251422

Hom.:

AF XY:

0.00302

AC XY:

411

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.00435

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00442

AC:

6462

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

3071

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00297

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00688

Gnomad4 NFE exome

AF:

0.00504

Gnomad4 OTH exome

AF:

0.00533

GnomAD4 genome

AF:

0.00311

AC:

474

AN:

152382

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00809

Gnomad4 NFE

AF:

0.00448

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00355

Hom.:

Bravo

AF:

0.00242

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00264

AC:

321

EpiCase

AF:

0.00409

EpiControl

AF:

0.00409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LONP1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Apr 26, 2017

BS1, BS2; This alteration has an allele frequency that is greater than expected for the associated disease, and was seen in a healthy adult where full penetrance of the disorder is expected at an early age. -

LONP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

See cases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 17, 2020

ACMG classification criteria: BS2, BP4 -

CODAS syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;.;.;T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D;D;D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.0092

T;T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.9

M;.;.;.;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.98

N;.;.;N;.;.

REVEL

Benign

0.26

Sift

Benign

0.039

D;.;.;D;.;.

Sift4G

Uncertain

0.039

D;D;D;T;T;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.67

MVP

0.40

MPC

0.94

ClinPred

0.048

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.27

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.

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