2-99162109-T-C

Position:

• chr2-99162109-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145199.3(LIPT1):​c.152T>C​(p.Ile51Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LIPT1 NM_145199.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

Genes affected

LIPT1 (HGNC:29569): (lipoyltransferase 1) The process of transferring lipoic acid to proteins is a two-step process. The first step is the activation of lipoic acid by lipoate-activating enzyme to form lipoyl-AMP. For the second step, the protein encoded by this gene transfers the lipoyl moiety to apoproteins. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 13. Read-through transcription also exists between this gene and the neighboring downstream mitochondrial ribosomal protein L30 (MRPL30) gene. [provided by RefSeq, Mar 2011]

MITD1 (HGNC:25207): (microtubule interacting and trafficking domain containing 1) Abscission, the separation of daughter cells at the end of cytokinesis, is effected by endosomal sorting complexes required for transport III (ESCRT-III). The protein encoded by this gene functions as a homodimer, with the N-termini binding to a subset of ESCRT-III subunits and the C-termini binding to membranes. The encoded protein regulates ESCRT-III activity and is required for proper cytokinesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPT1	NM_145199.3	c.152T>C	p.Ile51Thr	missense_variant	2/2	ENST00000651691.1	NP_660200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPT1	ENST00000651691.1	c.152T>C	p.Ile51Thr	missense_variant	2/2		NM_145199.3	ENSP00000498546	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 51 of the LIPT1 protein (p.Ile51Thr). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with LIPT1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	-0.069	T
MutationAssessor	Pathogenic	3.3	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.94
MutPred		0.73		Loss of stability (P = 0.0046);Loss of stability (P = 0.0046);Loss of stability (P = 0.0046);Loss of stability (P = 0.0046);Loss of stability (P = 0.0046);
MVP		0.74
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.55
gMVP		0.79

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: rs1574811318; hg19: chr2-99778572;