rs753904927

Positions:

chr11-74493327-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001144869.3(LIPT2):c.377T>G(p.Leu126Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,476,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

LIPT2
NM_001144869.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 2.46

Variant links:

Genes affected

LIPT2 (HGNC:37216): (lipoyl(octanoyl) transferase 2) This gene encodes a mitochondrial protein that catalyzes the transfer of octanoic acid to lipoate-dependent enzymes such as octanoyl-ACP. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

LIPT2 links:

LIPT2-AS1 (HGNC:56172): (LIPT2 antisense RNA 1)

LIPT2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

PP5

Variant 11-74493327-A-C is Pathogenic according to our data. Variant chr11-74493327-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 438639.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=1}. Variant chr11-74493327-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LIPT2	NM_001144869.3 linkuse as main transcript	c.377T>G	p.Leu126Arg	missense_variant	1/2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2 linkuse as main transcript	c.377T>G	p.Leu126Arg	missense_variant	1/2		NP_001316870.1
LIPT2	NM_001329942.2 linkuse as main transcript	c.237+140T>G		intron_variant			NP_001316871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LIPT2	ENST00000310109.5 linkuse as main transcript	c.377T>G	p.Leu126Arg	missense_variant	1/2	2	NM_001144869.3	ENSP00000309463	P1
LIPT2	ENST00000528085.1 linkuse as main transcript	c.181+140T>G		intron_variant		3		ENSP00000433005
LIPT2-AS1	ENST00000526036.1 linkuse as main transcript			upstream_gene_variant		1
LIPT2	ENST00000527115.1 linkuse as main transcript			upstream_gene_variant		2		ENSP00000431210

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

83428

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

47136

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000418

Gnomad OTH exome

AF:

0.000394

GnomAD4 exome

AF:

0.000313

AC:

414

AN:

1324416

Hom.:

Cov.:

AF XY:

0.000316

AC XY:

206

AN XY:

651230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000739

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000379

Gnomad4 OTH exome

AF:

0.000255

GnomAD4 genome

AF:

0.000190

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.000189

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:28757203). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:28757203). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:28757203). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 04, 2018	- -

LIPT2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2023

The LIPT2 c.377T>G variant is predicted to result in the amino acid substitution p.Leu126Arg. This variant was reported in a compound heterozygous individual with severe neonatal encephalopathy (Habarou et al 2017. PubMed ID: 28757203). Biochemical and functional studies support pathogenicity for the c.377T>C change (Lebigot E et al 2017. PubMed ID: 28803783). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-74204372-A-C). This variant is interpreted as likely pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 438639). This missense change has been observed in individuals with neonatal encephalopathy with lactic acidosis and brain anomalies (PMID: 28757203). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs753904927, gnomAD 0.04%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 126 of the LIPT2 protein (p.Leu126Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

0.69

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.031

Polyphen

0.98

Vest4

0.60

MVP

0.61

ClinPred

0.45

GERP RS

4.7

Varity_R

0.74

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over