2-99162029-T-TA
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_145199.3(LIPT1):c.79dup(p.Thr27AsnfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
LIPT1
NM_145199.3 frameshift
NM_145199.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.61
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-99162029-T-TA is Pathogenic according to our data. Variant chr2-99162029-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 452463.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LIPT1 | NM_145199.3 | c.79dup | p.Thr27AsnfsTer14 | frameshift_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.79dup | p.Thr27AsnfsTer14 | frameshift_variant | 2/2 | NM_145199.3 | ENSP00000498546 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152128Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251040Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135738
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461766Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727162
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152246Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 14, 2022 | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Thr27Asnfs*14) in the LIPT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 347 amino acid(s) of the LIPT1 protein. This variant has not been reported in the literature in individuals affected with LIPT1-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 452463). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 13, 2017 | The c.79dupA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.79dupA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.79dupA variant causes a frameshift starting with codon Threonine 27, changes this amino acid to an Asparagine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Thr27AsnfsX14. This variant is predicted to cause loss of normal protein function through protein truncation. In summary, we interpret this variant as likely pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at