4-39462269-C-T

Variant names:

• chr4-39462269-C-T
• rs796052702
• NM_006859.4:c.292C>T

Variant summary

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

The NM_006859.4(LIAS):​c.292C>T​(p.Arg98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000783 in 1,404,200 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: LIAS NM_006859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.778
• Publications: 1 publications found

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]

LIAS Gene-Disease associations (from GenCC):

• lipoic acid synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

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, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4	c.292C>T	p.Arg98Trp	missense_variant	Exon 3 of 11	ENST00000640888.2	NP_006850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.292C>T	p.Arg98Trp	missense_variant	Exon 3 of 11	1	NM_006859.4	ENSP00000492260.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000937 AC: 2 AN: 213502 AF XY: 0.0000172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000783 AC: 11 AN: 1404200 Hom.: 0 Cov.: 25 AF XY: 0.00000859 AC XY: 6 AN XY: 698588

African (AFR) AF: 0.00 AC: 0 AN: 30278

American (AMR) AF: 0.00 AC: 0 AN: 37258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25048

East Asian (EAS) AF: 0.00 AC: 0 AN: 35136

South Asian (SAS) AF: 0.00 AC: 0 AN: 78424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1082296

Other (OTH) AF: 0.00 AC: 0 AN: 57916

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000484 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lipoic acid synthetase deficiency Uncertain:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 98 of the LIAS protein (p.Arg98Trp). 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: 206045). 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 disruptive. 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.5	H;.;H;H;.;.
PhyloP100		0.78
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.3	.;.;D;D;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;.;D;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;D;.;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.71, 0.75
MutPred		0.48		Loss of disorder (P = 0.0249);Loss of disorder (P = 0.0249);Loss of disorder (P = 0.0249);Loss of disorder (P = 0.0249);Loss of disorder (P = 0.0249);.;
MVP		0.94
ClinPred		0.99	D
GERP RS		4.1
PromoterAI		-0.0022	Neutral
Varity_R		0.83
gMVP		0.84
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs796052702; hg19: chr4-39463889;