4-39459121-T-C

Position:

• chr4-39459121-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006859.4(LIAS):​c.4T>C​(p.Ser2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. S2C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LIAS NM_006859.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.678

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37744343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIAS	NM_006859.4	c.4T>C	p.Ser2Pro	missense_variant	1/11	ENST00000640888.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIAS	ENST00000640888.2	c.4T>C	p.Ser2Pro	missense_variant	1/11	1	NM_006859.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lipoic acid synthetase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 22, 2022

This variant has not been reported in the literature in individuals affected with LIAS-related conditions. 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. 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2 of the LIAS protein (p.Ser2Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T;.;T;.;.;.;.
Eigen	Benign	-0.082
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.5	L;.;.;L;.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.63	T
Polyphen		0.15	B;D;P;.;B;.;.;.;.
Vest4		0.57, 0.62, 0.56
MutPred		0.29		Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);Gain of catalytic residue at S2 (P = 0.0235);
MVP		0.81
MPC		0.53
ClinPred		0.82	D
GERP RS		4.0
Varity_R		0.22
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-39460741; COSMIC: COSV54695878; COSMIC: COSV54695878;