chr4-39459137-A-T

Position:

chr4-39459137-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006859.4(LIAS):c.20A>T(p.Asp7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.216

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04187846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIAS	NM_006859.4 linkuse as main transcript	c.20A>T	p.Asp7Val	missense_variant	1/11	ENST00000640888.2	NP_006850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 linkuse as main transcript	c.20A>T	p.Asp7Val	missense_variant	1/11	1	NM_006859.4	ENSP00000492260	P1	O43766-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250798

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135618

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461600

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727128

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:

0.0000809

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000452

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lipoic acid synthetase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 7 of the LIAS protein (p.Asp7Val). This variant is present in population databases (rs368786581, gnomAD 0.008%). 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: 859054). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 14, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.42

CADD

Benign

9.7

DANN

Benign

0.83

DEOGEN2

Benign

0.25

T;T;T;.;T;.;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.84

T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.042

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.1

N;.;.;N;.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.16

.;.;.;N;D;N;N;.;.

REVEL

Benign

0.099

Sift

Benign

0.14

.;.;.;T;T;T;T;.;.

Sift4G

Benign

0.072

.;.;.;T;T;T;T;.;.

Polyphen

0.0

B;B;B;.;B;.;.;.;.

Vest4

0.14, 0.18, 0.22, 0.20

MVP

0.64

MPC

0.55

ClinPred

0.029

GERP RS

0.23

Varity_R

0.092

gMVP

0.50

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