rs1172950083

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006859.4(LIAS):c.218G>C(p.Arg73Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,581,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R73G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.06

Publications

0 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4 link	c.218G>C	p.Arg73Thr	missense_variant, splice_region_variant	Exon 2 of 11	ENST00000640888.2	NP_006850.2	O43766-1A0A024R9W0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.218G>C	p.Arg73Thr	missense_variant, splice_region_variant	Exon 2 of 11	1	NM_006859.4	ENSP00000492260.1		O43766-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1429276

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708774

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31750

American (AMR)

AF:

0.00

AC:

AN:

37808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24884

East Asian (EAS)

AF:

0.00

AC:

AN:

39294

South Asian (SAS)

AF:

0.00

AC:

AN:

80300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1097938

Other (OTH)

AF:

0.00

AC:

AN:

58922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

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:

0.0000564

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lipoic acid synthetase deficiency

Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 73 of the LIAS protein (p.Arg73Thr). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 472878). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.78

D;T;T;.;T;.;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;T;D;D;D;T;D;T;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.59

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.054

MutationAssessor

Uncertain

2.3

M;.;.;M;.;.;M;.;.

PhyloP100

9.1

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.8

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

REVEL

Uncertain

0.55

Sift

Benign

0.13

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

Sift4G

Benign

0.18

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

Polyphen

0.99

D;D;D;.;D;.;.;.;.

Vest4

0.73, 0.80, 0.75, 0.76

MutPred

0.42

Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);Gain of phosphorylation at R73 (P = 0.044);

MVP

0.86

MPC

0.79

ClinPred

0.97

GERP RS

6.1

Varity_R

0.58

gMVP

0.80

Mutation Taster

=16/84

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over