11-74493420-C-T

Variant names:

• chr11-74493420-C-T
• rs1864397540
• NM_001144869.3:c.284G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001144869.3(LIPT2):​c.284G>A​(p.Gly95Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,357,536 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.62

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPT2	NM_001144869.3	c.284G>A	p.Gly95Asp	missense_variant	Exon 1 of 2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2	c.284G>A	p.Gly95Asp	missense_variant	Exon 1 of 2		NP_001316870.1
LIPT2	NM_001329942.2	c.237+47G>A		intron_variant	Intron 1 of 1		NP_001316871.1
LIPT2-AS1	NR_171028.1	n.41C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPT2	ENST00000310109.5	c.284G>A	p.Gly95Asp	missense_variant	Exon 1 of 2	2	NM_001144869.3	ENSP00000309463.4
LIPT2-AS1	ENST00000526036.1	n.55C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
LIPT2	ENST00000528085.1	c.180+47G>A		intron_variant	Intron 1 of 1	3		ENSP00000433005.1
LIPT2	ENST00000527115.1	c.-107G>A		upstream_gene_variant		2		ENSP00000431210.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1357536 Hom.: 0 Cov.: 43 AF XY: 0.00000299 AC XY: 2 AN XY: 669458

Gnomad4 AFR exome AF: 0.00

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: 0.00000187

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities Uncertain:2

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.95		Gain of relative solvent accessibility (P = 0.1259);
MVP		0.33
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1864397540; hg19: chr11-74204465; COSMIC: COSV59527275; COSMIC: COSV59527275;