2-99162763-G-C

Variant names:

• chr2-99162763-G-C
• rs863224892
• NM_145199.3:c.806G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145199.3(LIPT1):​c.806G>C​(p.Trp269Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W269C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIPT1 NM_145199.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.53
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

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.806G>C	p.Trp269Ser	missense	Exon 2 of 2	NP_660200.1	Q9Y234
	LIPT1	NM_001204830.2		c.806G>C	p.Trp269Ser	missense	Exon 3 of 3	NP_001191759.1	Q9Y234
	LIPT1	NM_015929.4		c.806G>C	p.Trp269Ser	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.806G>C	p.Trp269Ser	missense	Exon 2 of 2	ENSP00000498546.1	Q9Y234
	LIPT1	ENST00000393473.6	TSL:1	c.806G>C	p.Trp269Ser	missense	Exon 3 of 3	ENSP00000377115.2	Q9Y234
	ENSG00000273155	ENST00000410042.1	TSL:2	c.-28+6337G>C		intron	N/A	ENSP00000387111.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.71		Gain of disorder (P = 0.0042)
MVP		0.67
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
gMVP		0.95
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224892; hg19: chr2-99779226;