rs869320760

Positions:

• chr4-39465127-GAG-AAA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_006859.4(LIAS):​c.475_477delinsAAA​(p.Glu159Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIAS NM_006859.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.05

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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 4-39465127-GAG-AAA is Pathogenic according to our data. Variant chr4-39465127-GAG-AAA is described in ClinVar as [Pathogenic]. Clinvar id is 224601.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIAS	NM_006859.4	c.475_477delinsAAA	p.Glu159Lys	missense_variant	5/11	ENST00000640888.2	NP_006850.2
LIAS	NM_001278590.2	c.475_477delinsAAA	p.Glu159Lys	missense_variant	5/10		NP_001265519.1
LIAS	NM_194451.3	c.475_477delinsAAA	p.Glu159Lys	missense_variant	5/10		NP_919433.1
LIAS	NM_001363700.2	c.299+1522_299+1524delinsAAA		intron_variant			NP_001350629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.475_477delinsAAA	p.Glu159Lys	missense_variant	5/11	1	NM_006859.4	ENSP00000492260	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lipoic acid synthetase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs869320760; hg19: chr4-39466747;