19-5692181-C-T

Variant names:

• chr19-5692181-C-T
• rs1062373
• NM_004793.4:c.2731G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004793.4(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. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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 NM_004793.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.539
• Publications: 21 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1166716.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 = 0.02 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR,AD,XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	NM_004793.4	MANE Select	c.2731G>A	p.Val911Ile	missense	Exon 18 of 18	NP_004784.2
	LONP1	NM_001276479.2		c.2539G>A	p.Val847Ile	missense	Exon 19 of 19	NP_001263408.1	P36776-2
	LONP1	NM_001276480.1		c.2143G>A	p.Val715Ile	missense	Exon 18 of 18	NP_001263409.1	P36776-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	ENST00000360614.8	TSL:1 MANE Select	c.2731G>A	p.Val911Ile	missense	Exon 18 of 18	ENSP00000353826.2	P36776-1
	LONP1	ENST00000590729.5	TSL:1	c.2341G>A	p.Val781Ile	missense	Exon 18 of 18	ENSP00000465139.1	K7EJE8
	LONP1	ENST00000958482.1		c.2917G>A	p.Val973Ile	missense	Exon 19 of 19	ENSP00000628541.1

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3037 AN: 152186 Hom.: 53 Cov.: 33

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

GnomAD2 exomes AF: 0.0243 AC: 6093 AN: 250848 AF XY: 0.0239

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 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.: 34 AF XY: 0.0243 AC XY: 17677 AN XY: 727060

African (AFR) AF: 0.00320 AC: 107 AN: 33474

American (AMR) AF: 0.0285 AC: 1274 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 844 AN: 26088

East Asian (EAS) AF: 0.0270 AC: 1072 AN: 39696

South Asian (SAS) AF: 0.0165 AC: 1424 AN: 86230

European-Finnish (FIN) AF: 0.0247 AC: 1320 AN: 53358

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5764

European-Non Finnish (NFE) AF: 0.0250 AC: 27849 AN: 1111824

Other (OTH) AF: 0.0221 AC: 1332 AN: 60376

GnomAD4 genome AF: 0.0200 AC: 3043 AN: 152304 Hom.: 54 Cov.: 33 AF XY: 0.0194 AC XY: 1441 AN XY: 74460

African (AFR) AF: 0.00423 AC: 176 AN: 41572

American (AMR) AF: 0.0214 AC: 328 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3472

East Asian (EAS) AF: 0.0270 AC: 140 AN: 5180

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4826

European-Finnish (FIN) AF: 0.0242 AC: 257 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0278 AC: 1890 AN: 68016

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0257 Hom.: 148

Bravo AF: 0.0189

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00409 AC: 18

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	LONP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.13
DANN	Benign	0.93
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0036	T
PhyloP100		0.54
ClinPred		0.0028	T
GERP RS		-3.6
Varity_R		0.075
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1062373; hg19: chr19-5692192; COSMIC: COSV56798284; COSMIC: COSV56798284;