rs11085147

Variant names:

• chr19-5711919-C-A
• rs11085147
• NM_004793.4:c.722G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-5711919-C-A
• chr19-5711919-C-G
• chr19-5711919-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000360614.8(LONP1):​c.722G>T​(p.Arg241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R241Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LONP1 ENST00000360614.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360614.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	NM_004793.4	MANE Select	c.722G>T	p.Arg241Leu	missense	Exon 4 of 18	NP_004784.2
	LONP1	NM_001276479.2		c.530G>T	p.Arg177Leu	missense	Exon 5 of 19	NP_001263408.1
	LONP1	NM_001276480.1		c.134G>T	p.Arg45Leu	missense	Exon 4 of 18	NP_001263409.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	ENST00000360614.8	TSL:1 MANE Select	c.722G>T	p.Arg241Leu	missense	Exon 4 of 18	ENSP00000353826.2
	LONP1	ENST00000590729.5	TSL:1	c.380G>T	p.Arg127Leu	missense	Exon 4 of 18	ENSP00000465139.1
	LONP1	ENST00000593119.5	TSL:2	c.530G>T	p.Arg177Leu	missense	Exon 5 of 19	ENSP00000468541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461160 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.084
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.10
Sift	Benign	0.10	T
Sift4G	Benign	0.12	T
Polyphen		0.48	P
Vest4		0.55
MutPred		0.35		Loss of loop (P = 0.0288)
MVP		0.45
MPC		0.46
ClinPred		0.55	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.11
gMVP		0.51
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs11085147; hg19: chr19-5711930;