rs1190703859

Positions:

• chr11-74493390-A-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001144869.3(LIPT2):​c.314T>G​(p.Leu105Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000198 in 1,515,072 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L105V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.95

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-74493390-A-C is Pathogenic according to our data. Variant chr11-74493390-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-74493390-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPT2	NM_001144869.3	c.314T>G	p.Leu105Arg	missense_variant	1/2	ENST00000310109.5
LIPT2-AS1	NR_171028.1	n.11A>C		non_coding_transcript_exon_variant	1/2
LIPT2	NM_001329941.2	c.314T>G	p.Leu105Arg	missense_variant	1/2
LIPT2	NM_001329942.2	c.237+77T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPT2	ENST00000310109.5	c.314T>G	p.Leu105Arg	missense_variant	1/2	2	NM_001144869.3	P1
LIPT2-AS1	ENST00000526036.1	n.25A>C		non_coding_transcript_exon_variant	1/2	1
LIPT2	ENST00000528085.1	c.181+77T>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362864 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 672190

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: 9.34e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 04, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 15, 2017	- -
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). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:28757203). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.86		Gain of methylation at L105 (P = 0.0191);
MVP		0.57
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.97
gMVP		0.97

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

Other links and lift over

dbSNP: rs1190703859; hg19: chr11-74204435;