chr4-39471242-G-T

Position:

• chr4-39471242-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000640888.2(LIAS):​c.890G>T​(p.Arg297Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R297C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIAS ENST00000640888.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.36

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIAS	NM_006859.4	c.890G>T	p.Arg297Leu	missense_variant	9/11	ENST00000640888.2	NP_006850.2
LIAS	NM_001278590.2	c.761G>T	p.Arg254Leu	missense_variant	8/10		NP_001265519.1
LIAS	NM_194451.3	c.890G>T	p.Arg297Leu	missense_variant	9/10		NP_919433.1
LIAS	NM_001363700.2	c.581G>T	p.Arg194Leu	missense_variant	6/8		NP_001350629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.890G>T	p.Arg297Leu	missense_variant	9/11	1	NM_006859.4	ENSP00000492260	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;T;.;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.8	M;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.2	.;D;D;.;D;.;.;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	.;D;D;.;D;.;.;.
Sift4G	Uncertain	0.015	.;D;D;.;D;.;.;.
Polyphen		0.99	D;.;D;.;.;.;.;.
Vest4		0.89, 0.89, 0.91
MutPred		0.64		Loss of ubiquitination at K294 (P = 0.0578);.;.;.;Loss of ubiquitination at K294 (P = 0.0578);.;.;.;
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs756021613; hg19: chr4-39472862;