4-39459118-A-C

Variant names:

• chr4-39459118-A-C
• NM_006859.4:c.1A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_006859.4(LIAS):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LIAS NM_006859.4 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 86 codons. Genomic position: 39462233. Lost 0.229 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 11	ENST00000640888.2	NP_006850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 11	1	NM_006859.4	ENSP00000492260.1

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

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the LIAS mRNA. The next in-frame methionine is located at codon 86. This variant is not present in population databases (gnomAD no frequency). 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: 1443884). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T;T;T;.;T;.;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.77	T
PROVEAN	Benign	-0.51	.;.;.;N;N;N;N;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.14	.;.;.;T;D;T;T;.;.
Sift4G	Benign	0.45	.;.;.;T;T;T;T;.;.
Polyphen		0.0010	B;B;B;.;B;.;.;.;.
Vest4		0.81, 0.87, 0.82, 0.82
MutPred		0.98		Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);Loss of MoRF binding (P = 0.0769);
MVP		0.79
ClinPred		0.96	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.47
gMVP		0.48

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: chr4-39460738;