NM_006859.4:c.292C>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: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	NM_006859.4	MANE Select	c.292C>T	p.Arg98Trp	missense	Exon 3 of 11	NP_006850.2
	LIAS	NM_001278590.2		c.292C>T	p.Arg98Trp	missense	Exon 3 of 10	NP_001265519.1	O43766-3
	LIAS	NM_194451.3		c.292C>T	p.Arg98Trp	missense	Exon 3 of 10	NP_919433.1	O43766-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	ENST00000640888.2	TSL:1 MANE Select	c.292C>T	p.Arg98Trp	missense	Exon 3 of 11	ENSP00000492260.1	O43766-1
	LIAS	ENST00000424936.6	TSL:1	c.292C>T	p.Arg98Trp	missense	Exon 3 of 4	ENSP00000491086.1	Q6P5Q6
	LIAS	ENST00000946185.1		c.286C>T	p.Arg96Trp	missense	Exon 3 of 11	ENSP00000616244.1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Lipoic acid synthetase deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		0.78
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.48		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;