NM_145199.3:c.535A>G

Variant names:

• chr2-99162492-A-G
• rs786205156
• NM_145199.3:c.535A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_145199.3(LIPT1):​c.535A>G​(p.Thr179Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,818 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LIPT1 NM_145199.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.11
• Publications: 2 publications found

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]

ENSG00000273155 (HGNC:):

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity LIPT_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-99162492-A-G is Pathogenic according to our data. Variant chr2-99162492-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 189834.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145199.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT1	NM_145199.3	MANE Select	c.535A>G	p.Thr179Ala	missense	Exon 2 of 2	NP_660200.1	Q9Y234
	LIPT1	NM_001204830.2		c.535A>G	p.Thr179Ala	missense	Exon 3 of 3	NP_001191759.1	Q9Y234
	LIPT1	NM_015929.4		c.535A>G	p.Thr179Ala	missense	Exon 3 of 3	NP_057013.1	Q9Y234

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT1	ENST00000651691.1	MANE Select	c.535A>G	p.Thr179Ala	missense	Exon 2 of 2	ENSP00000498546.1	Q9Y234
	LIPT1	ENST00000393473.6	TSL:1	c.535A>G	p.Thr179Ala	missense	Exon 3 of 3	ENSP00000377115.2	Q9Y234
	ENSG00000273155	ENST00000410042.1	TSL:2	c.-28+6066A>G		intron	N/A	ENSP00000387111.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251430 AF XY: 0.00000736

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lipoyl transferase 1 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.89		Loss of sheet (P = 0.0817)
MVP		0.91
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.68
gMVP		0.87
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205156; hg19: chr2-99778955;