4-39467634-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006859.4(LIAS):​c.725C>T​(p.Pro242Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,427,304 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P242R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

3
14
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.80
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LIASNM_006859.4 linkuse as main transcriptc.725C>T p.Pro242Leu missense_variant 7/11 ENST00000640888.2
LIASNM_194451.3 linkuse as main transcriptc.725C>T p.Pro242Leu missense_variant 7/10
LIASNM_001363700.2 linkuse as main transcriptc.416C>T p.Pro139Leu missense_variant 4/8
LIASNM_001278590.2 linkuse as main transcriptc.608+2292C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LIASENST00000640888.2 linkuse as main transcriptc.725C>T p.Pro242Leu missense_variant 7/111 NM_006859.4 P1O43766-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000424
AC:
1
AN:
235888
Hom.:
0
AF XY:
0.00000779
AC XY:
1
AN XY:
128308
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000909
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000105
AC:
15
AN:
1427304
Hom.:
0
Cov.:
30
AF XY:
0.00000985
AC XY:
7
AN XY:
710482
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000119
Gnomad4 OTH exome
AF:
0.0000342
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Lipoic acid synthetase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 12, 2021This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 242 of the LIAS protein (p.Pro242Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 572391). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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
Benign
0.17
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
D;D;.;.;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Pathogenic
0.97
D;D;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.51
D;D;D;D;D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Pathogenic
3.2
M;.;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Uncertain
-2.5
.;N;.;N;.
REVEL
Uncertain
0.50
Sift
Uncertain
0.0040
.;D;.;D;.
Sift4G
Uncertain
0.0090
.;D;.;D;.
Polyphen
0.51
P;D;.;.;.
Vest4
0.50, 0.52
MutPred
0.46
Gain of stability (P = 0.025);.;.;Gain of stability (P = 0.025);.;
MVP
0.93
MPC
0.52
ClinPred
0.88
D
GERP RS
5.9
Varity_R
0.50
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746107734; hg19: chr4-39469254; API