dbSNP rs746107734: LIAS:p.Pro242Gln (chr4-39467634-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_006859.4(LIAS):c.725C>A(p.Pro242Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,427,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P242R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.80

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:

ENSG00000298383 (HGNC:):

ENSG00000298383 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_006859.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39712453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LIAS	NM_006859.4 link	c.725C>A	p.Pro242Gln	missense_variant	Exon 7 of 11	ENST00000640888.2	NP_006850.2
LIAS	NM_194451.3 link	c.725C>A	p.Pro242Gln	missense_variant	Exon 7 of 10		NP_919433.1
LIAS	NM_001363700.2 link	c.416C>A	p.Pro139Gln	missense_variant	Exon 4 of 8		NP_001350629.1
LIAS	NM_001278590.2 link	c.608+2292C>A		intron_variant	Intron 6 of 9		NP_001265519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.725C>A	p.Pro242Gln	missense_variant	Exon 7 of 11	1	NM_006859.4	ENSP00000492260.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427302

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710480

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32558

American (AMR)

AF:

0.00

AC:

AN:

40112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

38318

South Asian (SAS)

AF:

0.00

AC:

AN:

81274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093442

Other (OTH)

AF:

0.00

AC:

AN:

58400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;T;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.40

T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.1

M;.;.;M;.

PhyloP100

4.8

PrimateAI

Uncertain

0.50

PROVEAN

Benign

1.4

.;N;.;N;.

REVEL

Uncertain

0.36

Sift

Benign

0.035

.;D;.;D;.

Sift4G

Uncertain

0.046

.;D;.;T;.

Polyphen

0.0060

B;B;.;.;.

Vest4

0.48, 0.47

MutPred

0.44

Loss of ubiquitination at K247 (P = 0.1172);.;.;Loss of ubiquitination at K247 (P = 0.1172);.;

MVP

0.90

MPC

0.42

ClinPred

0.77

GERP RS

5.9

Varity_R

0.25

gMVP

0.74

Mutation Taster

=62/38

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over