chr2-99162325-AG-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_145199.3(LIPT1):c.369delG(p.Lys123AsnfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,613,298 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 0.00073 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00093 ( 0 hom. )
Consequence
LIPT1
NM_145199.3 frameshift
NM_145199.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.332
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 Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.671 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-99162325-AG-A is Pathogenic according to our data. Variant chr2-99162325-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420362.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=4}.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LIPT1 | ENST00000651691.1 | c.369delG | p.Lys123AsnfsTer8 | frameshift_variant | Exon 2 of 2 | NM_145199.3 | ENSP00000498546.1 | |||
| ENSG00000273155 | ENST00000410042.1 | c.-28+5900delG | intron_variant | Intron 2 of 5 | 2 | ENSP00000387111.1 | ||||
| ENSG00000241962 | ENST00000424491.5 | n.63+11807delG | intron_variant | Intron 4 of 13 | 2 | ENSP00000390891.1 |
Frequencies
GnomAD3 genomes 0.000729 AC: 111AN: 152234Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000576 AC: 144AN: 249988Hom.: 0 AF XY: 0.000547 AC XY: 74AN XY: 135246
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GnomAD4 exome AF: 0.000932 AC: 1362AN: 1461064Hom.: 0 Cov.: 32 AF XY: 0.000904 AC XY: 657AN XY: 726894
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GnomAD4 genome 0.000729 AC: 111AN: 152234Hom.: 0 Cov.: 31 AF XY: 0.000632 AC XY: 47AN XY: 74386
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Lipoyl transferase 1 deficiency Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected. (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (163 heterozygotes, 0 homozygotes). (P) 0507 - Identified variant type is not compatible with in silico predictions of pathogenicity. (N) 0600 - Variant is located in an annotated domain or motif. This truncation would result in the loss of part of the LpIa domain, including many active and catalytic sites (NCBI). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Several downstream truncating variants have been reported as pathogenic, with no functional evidence (PMID: 27247813, ClinVar). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. Variant reported as likely pathogenic with no evidence (ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
not provided Pathogenic:1Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 24, 2024 | Has not been previously published in association with LIPT1-related disorders to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 251 amino acid(s) are replaced with 7 different amino acid(s), and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 33531667) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change creates a premature translational stop signal (p.Lys123Asnfs*8) in the LIPT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 251 amino acid(s) of the LIPT1 protein. This variant is present in population databases (rs552120721, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LIPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 420362). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Hypotonia;C0029131:Abnormal optic nerve morphology;C1384666:Hearing impairment;C2315100:Failure to thrive;C4049796:Abnormal cardiovascular system morphology Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 29, 2016 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 22, 2024 | Variant summary: LIPT1 c.369delG (p.Lys123AsnfsX8) results in a premature termination codon and is predicted to cause a truncation of the encoded protein. Although the variant is not expected to cause nonsense mediated decay, the variant disrupts the last 251 amino acids of the LIPT1 protein, including those within the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domains (IPR004143). A truncation downstream of this position has been classified as pathogenic within ClinVar (e.g. c.875C>G [p.Ser292Ter]). However, the variant allele was found at a frequency of 0.00091 in 1613298 control chromosomes in the gnomAD database. To our knowledge, no occurrence of c.369delG in individuals affected with Lipoyl Transferase 1 Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 420362). Based on the conflicting evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at