rs11085147

Positions:

• chr19-5711919-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/20 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.

• Frequency:
  • Genomes: 𝑓 0.057 (361 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5819 hom.)
• Consequence: LONP1 NM_004793.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.02

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
LONP1	NM_004793.4	c.722G>A	p.Arg241Gln	missense_variant	4/18	ENST00000360614.8	NP_004784.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LONP1	ENST00000360614.8	c.722G>A	p.Arg241Gln	missense_variant	4/18	1	NM_004793.4	ENSP00000353826	P1

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8637 AN: 152168 Hom.: 361 Cov.: 32

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

GnomAD3 exomes AF: 0.0563 AC: 14109 AN: 250662 Hom.: 566 AF XY: 0.0561 AC XY: 7606 AN XY: 135684

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 SAS exome AF: 0.0133

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.: 32 AF XY: 0.0801 AC XY: 58234 AN XY: 726960

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0274

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0805

Gnomad4 NFE exome AF: 0.0977

Gnomad4 OTH exome AF: 0.0697

GnomAD4 genome AF: 0.0567 AC: 8634 AN: 152286 Hom.: 361 Cov.: 32 AF XY: 0.0550 AC XY: 4093 AN XY: 74454

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0357

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00993

Gnomad4 FIN AF: 0.0817

Gnomad4 NFE AF: 0.0920

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0769 Hom.: 1236

Bravo AF: 0.0519

TwinsUK AF: 0.0949 AC: 352

ALSPAC AF: 0.0978 AC: 377

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.0916 AC: 788

ExAC AF: 0.0590 AC: 7158

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0794

EpiControl AF: 0.0734

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
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	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.;.;.
MutationTaster	Benign	0.077	P;P;P;P;P
PrimateAI	Benign	0.40	T
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	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.037
gMVP		0.43

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

Other links and lift over

dbSNP: rs11085147; hg19: chr19-5711930; COSMIC: COSV62261274; COSMIC: COSV62261274;