rs750744754

chr4-39467655-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006859.4(LIAS):c.737+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,533,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: LIAS NM_006859.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.41

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-39467655-G-A is Benign according to our data. Variant chr4-39467655-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472882.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIAS	NM_006859.4	c.737+9G>A		intron_variant		ENST00000640888.2
LIAS	NM_001278590.2	c.608+2313G>A		intron_variant
LIAS	NM_001363700.2	c.428+9G>A		intron_variant
LIAS	NM_194451.3	c.737+9G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIAS	ENST00000640888.2	c.737+9G>A		intron_variant		1	NM_006859.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000730 AC: 16 AN: 219072 Hom.: 0 AF XY: 0.0000920 AC XY: 11 AN XY: 119518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000123

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.0000956

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.000127 AC: 176 AN: 1381514 Hom.: 0 Cov.: 30 AF XY: 0.000126 AC XY: 86 AN XY: 684414

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000281

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000807

Gnomad4 FIN exome AF: 0.0000394

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.0000713

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lipoic acid synthetase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.0030
Dann	Benign	0.79

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: rs750744754; hg19: chr4-39469275;