rs869312808

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006859.4(LIAS):c.645T>A(p.Asp215Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,608,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D215N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.58

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:

ENSG00000298383 (HGNC:):

ENSG00000298383 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4 link	c.645T>A	p.Asp215Glu	missense_variant	Exon 7 of 11	ENST00000640888.2	NP_006850.2	O43766-1A0A024R9W0
LIAS	NM_194451.3 link	c.645T>A	p.Asp215Glu	missense_variant	Exon 7 of 10		NP_919433.1	O43766-2
LIAS	NM_001363700.2 link	c.336T>A	p.Asp112Glu	missense_variant	Exon 4 of 8		NP_001350629.1
LIAS	NM_001278590.2 link	c.608+2212T>A		intron_variant	Intron 6 of 9		NP_001265519.1	O43766-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.645T>A	p.Asp215Glu	missense_variant	Exon 7 of 11	1	NM_006859.4	ENSP00000492260.1		O43766-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

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:

0.00000687

AC:

AN:

1456066

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33330

American (AMR)

AF:

0.00

AC:

AN:

43580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

85414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000811

AC:

AN:

1109256

Other (OTH)

AF:

0.0000167

AC:

AN:

60056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lipoic acid synthetase deficiency

Pathogenic:1Uncertain:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 215 of the LIAS protein (p.Asp215Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nonketotic hyperglycinemia (PMID: 24334290). ClinVar contains an entry for this variant (Variation ID: 224602). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LIAS protein function with a positive predictive value of 80%. 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. -

Mar 20, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

4.5

H;.;.;H;.

PhyloP100

2.6

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.8

.;D;.;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

.;D;.;D;.

Sift4G

Uncertain

0.0020

.;D;.;D;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.95, 0.94

MutPred

0.86

Gain of sheet (P = 0.1539);.;.;Gain of sheet (P = 0.1539);.;

MVP

0.87

MPC

1.2

ClinPred

1.0

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.94

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over