4-39459122-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006859.4(LIAS):c.5C>G(p.Ser2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,774 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. S2F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LIAS NM_006859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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]

ACMG classification

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.5C>G	p.Ser2Cys	missense_variant	1/11	ENST00000640888.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIAS	ENST00000640888.2	c.5C>G	p.Ser2Cys	missense_variant	1/11	1	NM_006859.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lipoic acid synthetase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;T;.;T;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.5	L;.;.;L;.;.;L;.;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Uncertain	0.63	T
Polyphen		0.38	B;D;P;.;B;.;.;.;.
Vest4		0.50, 0.53, 0.49, 0.49
MutPred		0.35		Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);
MVP		0.88
MPC		0.48
ClinPred		0.95	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.27
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-39460742;