rs751421705

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006859.4(LIAS):c.473G>C(p.Ser158Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.64

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0905067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LIAS	NM_006859.4 linkuse as main transcript	c.473G>C	p.Ser158Thr	missense_variant	5/11	ENST00000640888.2
LIAS	NM_001278590.2 linkuse as main transcript	c.473G>C	p.Ser158Thr	missense_variant	5/10
LIAS	NM_194451.3 linkuse as main transcript	c.473G>C	p.Ser158Thr	missense_variant	5/10
LIAS	NM_001363700.2 linkuse as main transcript	c.299+1520G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIAS	ENST00000640888.2 linkuse as main transcript	c.473G>C	p.Ser158Thr	missense_variant	5/11	1	NM_006859.4	P1	O43766-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251450

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135904

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727238

show subpopulations

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:

0.0000387

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

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

Sep 02, 2021

This sequence change replaces serine with threonine at codon 158 of the LIAS protein (p.Ser158Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs751421705, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with LIAS-related conditions. 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.41

Cadd

Benign

8.0

Dann

Benign

0.89

DEOGEN2

Uncertain

0.43

T;.;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.091

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.43

N;N;N;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.23

Polyphen

0.0010

B;.;.;.

Vest4

0.24, 0.22

MutPred

0.36

Gain of phosphorylation at S158 (P = 0.0654);Gain of phosphorylation at S158 (P = 0.0654);Gain of phosphorylation at S158 (P = 0.0654);.;

MVP

0.62

ClinPred

0.029

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.068

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over