rs753904927

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3PP3_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). ClinVar reports functional evidence for this variant: "SCV000787469: "Well-established functional studies show a deleterious effect" (PMID:28757203)." and additional evidence is available in ClinVar.

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:2

Conservation

PhyloP100: 2.46

Publications

3 publications found

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

new If you want to explore the variant's impact on the transcript NM_001144869.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000787469: "Well-established functional studies show a deleterious effect" (PMID:28757203).; SCV004111724: Biochemical and functional studies support pathogenicity for the c.377T>C change (Lebigot E et al 2017. PubMed ID: 28803783).

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 VariationId is 438639.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144869.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIPT2	NM_001144869.3	MANE Select	c.377T>G	p.Leu126Arg	missense	Exon 1 of 2	NP_001138341.1	A6NK58
LIPT2	NM_001329941.2		c.377T>G	p.Leu126Arg	missense	Exon 1 of 2	NP_001316870.1
LIPT2	NM_001329942.2		c.237+140T>G		intron	N/A	NP_001316871.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIPT2	ENST00000310109.5	TSL:2 MANE Select	c.377T>G	p.Leu126Arg	missense	Exon 1 of 2	ENSP00000309463.4	A6NK58
LIPT2	ENST00000528085.1	TSL:3	c.180+140T>G		intron	N/A	ENSP00000433005.1	H0YD50
LIPT2-AS1	ENST00000526036.1	TSL:1	n.-39A>C		upstream_gene	N/A

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

GnomAD2 exomes

AF:

0.000168

AC:

AN:

83428

AF XY:

0.000149

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 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

African (AFR)

AF:

0.0000739

AC:

AN:

27054

American (AMR)

AF:

0.00

AC:

AN:

28240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22718

East Asian (EAS)

AF:

0.00

AC:

AN:

30782

South Asian (SAS)

AF:

0.00

AC:

AN:

72772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4860

European-Non Finnish (NFE)

AF:

0.000379

AC:

398

AN:

1050412

Other (OTH)

AF:

0.000255

AC:

AN:

54998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000190

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.000189

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (3)

LIPT2-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

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

PhyloP100

2.5

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.031

PromoterAI

-0.19

Neutral

(source)

Varity_R

0.74

gMVP

0.93

Mutation Taster

=27/73

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over