Genetic Variant NM_004793.4:c.2353A>G (chr19-5693737-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_004793.4(LONP1):c.2353A>G(p.Arg785Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

LONP1
NM_004793.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.866

Publications

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

LONP1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-5693737-T-C is Pathogenic according to our data. Variant chr19-5693737-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 180657.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004793.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LONP1	NM_004793.4	MANE Select	c.2353A>G	p.Arg785Gly	missense	Exon 16 of 18	NP_004784.2
LONP1	NM_001276479.2		c.2161A>G	p.Arg721Gly	missense	Exon 17 of 19	NP_001263408.1	P36776-2
LONP1	NM_001276480.1		c.1765A>G	p.Arg589Gly	missense	Exon 16 of 18	NP_001263409.1	P36776-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LONP1	ENST00000360614.8	TSL:1 MANE Select	c.2353A>G	p.Arg785Gly	missense	Exon 16 of 18	ENSP00000353826.2	P36776-1
LONP1	ENST00000590729.5	TSL:1	c.1963A>G	p.Arg655Gly	missense	Exon 16 of 18	ENSP00000465139.1	K7EJE8
LONP1	ENST00000958482.1		c.2539A>G	p.Arg847Gly	missense	Exon 17 of 19	ENSP00000628541.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CODAS syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.9

PhyloP100

0.87

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.32

Sift

Benign

0.14

Sift4G

Benign

0.21

Polyphen

0.97

Vest4

0.76

MutPred

0.49

Gain of helix (P = 0.062)

MVP

0.78

MPC

0.88

ClinPred

0.97

GERP RS

0.066

Varity_R

0.77

gMVP

0.90

Mutation Taster

=8/92

disease causing (ClinVar)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over