chr19-5711919-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R241R) has been classified as Likely benign.

• 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
• Publications: 33 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: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LONP1	NM_004793.4	MANE Select	c.722G>A	p.Arg241Gln	missense	Exon 4 of 18	NP_004784.2
	LONP1	NM_001276479.2		c.530G>A	p.Arg177Gln	missense	Exon 5 of 19	NP_001263408.1
	LONP1	NM_001276480.1		c.134G>A	p.Arg45Gln	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>A	p.Arg241Gln	missense	Exon 4 of 18	ENSP00000353826.2
	LONP1	ENST00000590729.5	TSL:1	c.380G>A	p.Arg127Gln	missense	Exon 4 of 18	ENSP00000465139.1
	LONP1	ENST00000958482.1		c.722G>A	p.Arg241Gln	missense	Exon 4 of 19	ENSP00000628541.1

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

GnomAD2 exomes AF: 0.0563 AC: 14109 AN: 250662 AF XY: 0.0561

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 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

African (AFR) AF: 0.0121 AC: 406 AN: 33478

American (AMR) AF: 0.0249 AC: 1115 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 717 AN: 26124

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39694

South Asian (SAS) AF: 0.0134 AC: 1159 AN: 86258

European-Finnish (FIN) AF: 0.0805 AC: 4249 AN: 52770

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5766

European-Non Finnish (NFE) AF: 0.0977 AC: 108681 AN: 1111946

Other (OTH) AF: 0.0697 AC: 4211 AN: 60382

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

African (AFR) AF: 0.0165 AC: 687 AN: 41576

American (AMR) AF: 0.0357 AC: 546 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00993 AC: 48 AN: 4832

European-Finnish (FIN) AF: 0.0817 AC: 868 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0920 AC: 6255 AN: 68018

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0741 Hom.: 1544

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.071
Sift	Benign	0.25	T
Sift4G	Benign	0.26	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
Mutation Taster		=97/3	polymorphism (auto)

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; COSMIC: COSV62261274; COSMIC: COSV62261274;