19-5692181-C-T

Position:

chr19-5692181-C-T

Variant summary

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

The ENST00000360614.8(LONP1):c.2731G>A(p.Val911Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,613,802 control chromosomes in the GnomAD database, including 567 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V911L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.020 ( 54 hom., cov: 33)

Exomes 𝑓: 0.024 ( 513 hom. )

Consequence

LONP1
ENST00000360614.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.539

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:

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=0.0036029816).

BP6

Variant 19-5692181-C-T is Benign according to our data. Variant chr19-5692181-C-T is described in ClinVar as [Benign]. Clinvar id is 1166716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-5692181-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.02 (3043/152304) while in subpopulation NFE AF= 0.0278 (1890/68016). AF 95% confidence interval is 0.0267. There are 54 homozygotes in gnomad4. There are 1441 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LONP1	NM_004793.4 linkuse as main transcript	c.2731G>A	p.Val911Ile	missense_variant	18/18	ENST00000360614.8	NP_004784.2
LONP1	NM_001276479.2 linkuse as main transcript	c.2539G>A	p.Val847Ile	missense_variant	19/19		NP_001263408.1
LONP1	NM_001276480.1 linkuse as main transcript	c.2143G>A	p.Val715Ile	missense_variant	18/18		NP_001263409.1
LONP1	NR_076392.2 linkuse as main transcript	n.2536G>A		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONP1	ENST00000360614.8 linkuse as main transcript	c.2731G>A	p.Val911Ile	missense_variant	18/18	1	NM_004793.4	ENSP00000353826	P1	P36776-1

Frequencies

GnomAD3 genomes

AF:

0.0200

AC:

3037

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.0266

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0242

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0278

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.0243

AC:

6093

AN:

250848

Hom.:

AF XY:

0.0239

AC XY:

3246

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.0302

Gnomad ASJ exome

AF:

0.0321

Gnomad EAS exome

AF:

0.0262

Gnomad SAS exome

AF:

0.0143

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0241

AC:

35288

AN:

1461498

Hom.:

513

Cov.:

AF XY:

0.0243

AC XY:

17677

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.0285

Gnomad4 ASJ exome

AF:

0.0324

Gnomad4 EAS exome

AF:

0.0270

Gnomad4 SAS exome

AF:

0.0165

Gnomad4 FIN exome

AF:

0.0247

Gnomad4 NFE exome

AF:

0.0250

Gnomad4 OTH exome

AF:

0.0221

GnomAD4 genome

AF:

0.0200

AC:

3043

AN:

152304

Hom.:

Cov.:

AF XY:

0.0194

AC XY:

1441

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00423

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.0337

Gnomad4 EAS

AF:

0.0270

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.0242

Gnomad4 NFE

AF:

0.0278

Gnomad4 OTH

AF:

0.0198

Alfa

AF:

0.0239

Hom.:

Bravo

AF:

0.0189

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0273

AC:

235

ExAC

AF:

0.0237

AC:

2874

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

EpiCase

AF:

0.0269

EpiControl

AF:

0.0211

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2019	This variant is associated with the following publications: (PMID: 20843780) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

LONP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.13

DANN

Benign

0.93

DEOGEN2

Benign

0.013

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0036

MutationTaster

Benign

0.98

N;N;N;N;N

ClinPred

0.0028

GERP RS

-3.6

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