rs140921822

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006859.4(LIAS):c.57A>C(p.Arg19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,574,312 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 7 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.590

Publications

1 publications found

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 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

LIAS links:

ENSG00000298395 (HGNC:):

ENSG00000298395 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059530437).

BP6

Variant 4-39460801-A-C is Benign according to our data. Variant chr4-39460801-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 378084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00334 (508/152256) while in subpopulation AFR AF = 0.0117 (487/41544). AF 95% confidence interval is 0.0109. There are 2 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4 link	c.57A>C	p.Arg19Ser	missense_variant	Exon 2 of 11	ENST00000640888.2	NP_006850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.57A>C	p.Arg19Ser	missense_variant	Exon 2 of 11	1	NM_006859.4	ENSP00000492260.1

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

508

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.00192

GnomAD2 exomes

AF:

0.000808

AC:

179

AN:

221586

AF XY:

0.000532

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000568

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.000317

AC:

451

AN:

1422056

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

209

AN XY:

706012

show subpopulations

African (AFR)

AF:

0.0120

AC:

376

AN:

31244

American (AMR)

AF:

0.000229

AC:

AN:

34976

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24178

East Asian (EAS)

AF:

0.00

AC:

AN:

39340

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52532

Middle Eastern (MID)

AF:

0.000358

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00000638

AC:

AN:

1097132

Other (OTH)

AF:

0.000974

AC:

AN:

58526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00334

AC:

508

AN:

152256

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0117

AC:

487

AN:

41544

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.00374

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 07, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Oct 24, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Lipoic acid synthetase deficiency

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 14, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

LIAS-related disorder

Benign:1

Aug 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.5

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.26

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

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.84

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

MetaRNN

Benign

0.0060

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.40

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

PhyloP100

0.59

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.28

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

REVEL

Benign

0.10

Sift

Benign

0.17

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

Sift4G

Benign

0.50

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

Polyphen

0.0

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

Vest4

0.32, 0.18, 0.33, 0.33

MutPred

0.44

Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);Loss of MoRF binding (P = 0.0147);

MVP

0.68

MPC

0.43

ClinPred

0.0079

GERP RS

0.86

Varity_R

0.074

gMVP

0.58

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over