4-39467634-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006859.4(LIAS):c.725C>T(p.Pro242Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,427,304 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P242R) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
LIAS
NM_006859.4 missense
NM_006859.4 missense
Scores
3
14
2
Clinical Significance
Conservation
PhyloP100: 4.80
Genes affected
LIAS (HGNC:16429): (lipoic acid synthetase) The protein encoded by this gene belongs to the biotin and lipoic acid synthetases family. Localized in the mitochondrion, this iron-sulfur enzyme catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. The deficient expression of this enzyme has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy. Alternative splicing occurs at this locus, and several transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Aug 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIAS | NM_006859.4 | c.725C>T | p.Pro242Leu | missense_variant | 7/11 | ENST00000640888.2 | |
LIAS | NM_194451.3 | c.725C>T | p.Pro242Leu | missense_variant | 7/10 | ||
LIAS | NM_001363700.2 | c.416C>T | p.Pro139Leu | missense_variant | 4/8 | ||
LIAS | NM_001278590.2 | c.608+2292C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIAS | ENST00000640888.2 | c.725C>T | p.Pro242Leu | missense_variant | 7/11 | 1 | NM_006859.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000424 AC: 1AN: 235888Hom.: 0 AF XY: 0.00000779 AC XY: 1AN XY: 128308
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GnomAD4 exome AF: 0.0000105 AC: 15AN: 1427304Hom.: 0 Cov.: 30 AF XY: 0.00000985 AC XY: 7AN XY: 710482
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lipoic acid synthetase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2021 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 242 of the LIAS protein (p.Pro242Leu). 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 variant has not been reported in the literature in individuals affected with LIAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 572391). 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 tolerated. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;N;.;N;.
REVEL
Uncertain
Sift
Uncertain
.;D;.;D;.
Sift4G
Uncertain
.;D;.;D;.
Polyphen
P;D;.;.;.
Vest4
0.50, 0.52
MutPred
Gain of stability (P = 0.025);.;.;Gain of stability (P = 0.025);.;
MVP
0.93
MPC
0.52
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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