rs869312808
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_006859.4(LIAS):c.645T>A(p.Asp215Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,608,290 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
LIAS
NM_006859.4 missense
NM_006859.4 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 2.58
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 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.905
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LIAS | NM_006859.4 | c.645T>A | p.Asp215Glu | missense_variant | 7/11 | ENST00000640888.2 | NP_006850.2 | |
LIAS | NM_194451.3 | c.645T>A | p.Asp215Glu | missense_variant | 7/10 | NP_919433.1 | ||
LIAS | NM_001363700.2 | c.336T>A | p.Asp112Glu | missense_variant | 4/8 | NP_001350629.1 | ||
LIAS | NM_001278590.2 | c.608+2212T>A | intron_variant | NP_001265519.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIAS | ENST00000640888.2 | c.645T>A | p.Asp215Glu | missense_variant | 7/11 | 1 | NM_006859.4 | ENSP00000492260.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000687 AC: 10AN: 1456066Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4AN XY: 724566
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Lipoic acid synthetase deficiency Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 215 of the LIAS protein (p.Asp215Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 24334290). ClinVar contains an entry for this variant (Variation ID: 224602). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LIAS protein function with a positive predictive value of 80%. 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
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
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
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;H;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;.;D;.
Sift4G
Uncertain
.;D;.;D;.
Polyphen
D;D;.;.;.
Vest4
0.95, 0.94
MutPred
Gain of sheet (P = 0.1539);.;.;Gain of sheet (P = 0.1539);.;
MVP
0.87
MPC
1.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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