rs539962457

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001144869.3(LIPT2):c.89T>C(p.Leu30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,456,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L30V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 35)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

LIPT2
NM_001144869.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.60

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-74493615-A-G is Pathogenic according to our data. Variant chr11-74493615-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438640.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-74493615-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LIPT2	NM_001144869.3 linkuse as main transcript	c.89T>C	p.Leu30Pro	missense_variant	1/2	ENST00000310109.5
LIPT2-AS1	NR_171028.1 linkuse as main transcript	n.236A>G		non_coding_transcript_exon_variant	1/2
LIPT2	NM_001329941.2 linkuse as main transcript	c.89T>C	p.Leu30Pro	missense_variant	1/2
LIPT2	NM_001329942.2 linkuse as main transcript	c.89T>C	p.Leu30Pro	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LIPT2	ENST00000310109.5 linkuse as main transcript	c.89T>C	p.Leu30Pro	missense_variant	1/2	2	NM_001144869.3	P1
LIPT2-AS1	ENST00000526036.1 linkuse as main transcript	n.250A>G		non_coding_transcript_exon_variant	1/2	1
LIPT2	ENST00000528085.1 linkuse as main transcript	c.35T>C	p.Leu12Pro	missense_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000383

AC:

AN:

1304740

Hom.:

Cov.:

AF XY:

0.00000467

AC XY:

AN XY:

641812

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

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:

0.00000192

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000192

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities

Pathogenic:2

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: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:28757203). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:28757203). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.30

Eigen

Benign

0.023

Eigen_PC

Benign

-0.032

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.68

Sift

Benign

0.11

Sift4G

Benign

0.12

Polyphen

0.90

Vest4

0.37

MutPred

0.66

Gain of disorder (P = 0.0084);

MVP

0.59

ClinPred

0.94

GERP RS

3.6

Varity_R

0.68

gMVP

0.83

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

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