11-74493378-C-T

Position:

• chr11-74493378-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144869.3(LIPT2):​c.326G>A​(p.Gly109Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000514 in 1,361,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.978

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2713813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPT2	NM_001144869.3	c.326G>A	p.Gly109Asp	missense_variant	1/2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2	c.326G>A	p.Gly109Asp	missense_variant	1/2		NP_001316870.1
LIPT2	NM_001329942.2	c.237+89G>A		intron_variant			NP_001316871.1
LIPT2-AS1	NR_171028.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPT2	ENST00000310109.5	c.326G>A	p.Gly109Asp	missense_variant	1/2	2	NM_001144869.3	ENSP00000309463	P1
LIPT2-AS1	ENST00000526036.1	n.13C>T		non_coding_transcript_exon_variant	1/2	1
LIPT2	ENST00000528085.1	c.181+89G>A		intron_variant		3		ENSP00000433005

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000514 AC: 7 AN: 1361210 Hom.: 0 Cov.: 42 AF XY: 0.00000596 AC XY: 4 AN XY: 671296

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: 0.00000374

Gnomad4 OTH exome AF: 0.0000351

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.G109D in LIPT2 (NM_001144869.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.G109D variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G109D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.326 in LIPT2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.G109D in LIPT2 (NM_001144869.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.G109D variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.G109D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.326 in LIPT2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2022

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: "Benign"; Align-GVGD: "Not Available"). 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. This variant has not been reported in the literature in individuals affected with LIPT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 109 of the LIPT2 protein (p.Gly109Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.95	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.18	N
REVEL	Uncertain	0.59
Sift	Benign	0.45	T
Sift4G	Benign	0.41	T
Polyphen		0.089	B
Vest4		0.25
MutPred		0.42		Loss of MoRF binding (P = 0.0286);
MVP		0.13
ClinPred		0.29	T
GERP RS		4.7
Varity_R		0.20
gMVP		0.54

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: rs562535449; hg19: chr11-74204423;