rs546751789

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_Moderate

The NM_006859.4(LIAS):c.737+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,566,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

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

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

LIAS
NM_006859.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.53

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: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1152815 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP5

Variant 4-39467647-G-A is Pathogenic according to our data. Variant chr4-39467647-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 572236.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4 link	c.737+1G>A	splice_donor_variant, intron_variant	Intron 7 of 10	ENST00000640888.2	NP_006850.2	O43766-1A0A024R9W0
LIAS	NM_001278590.2 link	c.608+2305G>A	intron_variant	Intron 6 of 9		NP_001265519.1	O43766-3
LIAS	NM_194451.3 link	c.737+1G>A	splice_donor_variant, intron_variant	Intron 7 of 9		NP_919433.1	O43766-2
LIAS	NM_001363700.2 link	c.428+1G>A	splice_donor_variant, intron_variant	Intron 4 of 7		NP_001350629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.737+1G>A		splice_donor_variant, intron_variant	Intron 7 of 10	1	NM_006859.4	ENSP00000492260.1		O43766-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000259

AC:

AN:

231510

AF XY:

0.0000317

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1414212

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

702990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32246

American (AMR)

AF:

0.00

AC:

AN:

38450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24788

East Asian (EAS)

AF:

0.00

AC:

AN:

37990

South Asian (SAS)

AF:

0.000214

AC:

AN:

79338

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086040

Other (OTH)

AF:

0.0000346

AC:

AN:

57782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.0000131

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2110

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:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lipoic acid synthetase deficiency

Pathogenic:1

Aug 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals affected with LIAS-related conditions. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 572236). This variant is present in population databases (rs546751789, gnomAD 0.02%). This sequence change affects a donor splice site in intron 7 of the LIAS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LIAS are known to be pathogenic (PMID: 24334290, 27923773). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Uncertain

0.95

PhyloP100

9.5

GERP RS

5.9

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: 16

DS_DL_spliceai

0.98

Position offset: -1

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