NM_006859.4:c.403G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_006859.4(LIAS):​c.403G>A​(p.Asp135Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,582 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D135H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

7
9
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.05

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1
In a domain Radical SAM core (size 219) in uniprot entity LIAS_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_006859.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LIASNM_006859.4 linkc.403G>A p.Asp135Asn missense_variant Exon 5 of 11 ENST00000640888.2 NP_006850.2 O43766-1A0A024R9W0
LIASNM_001278590.2 linkc.403G>A p.Asp135Asn missense_variant Exon 5 of 10 NP_001265519.1 O43766-3
LIASNM_194451.3 linkc.403G>A p.Asp135Asn missense_variant Exon 5 of 10 NP_919433.1 O43766-2
LIASNM_001363700.2 linkc.299+1450G>A intron_variant Intron 3 of 7 NP_001350629.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LIASENST00000640888.2 linkc.403G>A p.Asp135Asn missense_variant Exon 5 of 11 1 NM_006859.4 ENSP00000492260.1 O43766-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250510
AF XY:
0.00
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:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460582
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726568
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33436
American (AMR)
AF:
0.00
AC:
0
AN:
44542
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26080
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86042
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111306
Other (OTH)
AF:
0.00
AC:
0
AN:
60324
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Benign
-0.22
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.84
D;.;.;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Benign
0.078
D
MetaRNN
Uncertain
0.73
D;D;D;D
MetaSVM
Uncertain
0.28
D
MutationAssessor
Uncertain
2.4
M;M;M;.
PhyloP100
9.0
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.8
.;D;D;.
REVEL
Uncertain
0.59
Sift
Uncertain
0.0030
.;D;D;.
Sift4G
Uncertain
0.031
.;D;D;.
Polyphen
1.0
D;.;.;.
Vest4
0.83, 0.83
MutPred
0.56
Gain of MoRF binding (P = 0.0424);Gain of MoRF binding (P = 0.0424);Gain of MoRF binding (P = 0.0424);.;
MVP
0.95
ClinPred
0.97
D
GERP RS
6.1
Varity_R
0.80
gMVP
0.89
Mutation Taster
=10/90
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs772011702; hg19: chr4-39466675; API