4-39465159-A-G

Position:

• chr4-39465159-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006859.4(LIAS):​c.507A>G​(p.Glu169=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,614,172 control chromosomes in the GnomAD database, including 6,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (310 hom., cov: 33)
  • Exomes 𝑓: 0.085 (5998 hom.)
• Consequence: LIAS NM_006859.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-39465159-A-G is Benign according to our data. Variant chr4-39465159-A-G is described in ClinVar as [Benign]. Clinvar id is 138122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.678 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIAS	NM_006859.4	c.507A>G	p.Glu169=	synonymous_variant	5/11	ENST00000640888.2	NP_006850.2
LIAS	NM_001278590.2	c.507A>G	p.Glu169=	synonymous_variant	5/10		NP_001265519.1
LIAS	NM_194451.3	c.507A>G	p.Glu169=	synonymous_variant	5/10		NP_919433.1
LIAS	NM_001363700.2	c.299+1554A>G		intron_variant			NP_001350629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.507A>G	p.Glu169=	synonymous_variant	5/11	1	NM_006859.4	ENSP00000492260	P1

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8530 AN: 152246 Hom.: 311 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0503

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0891

Gnomad OTH AF: 0.0415

GnomAD3 exomes AF: 0.0605 AC: 15205 AN: 251388 Hom.: 608 AF XY: 0.0627 AC XY: 8514 AN XY: 135862

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0518

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0851

Gnomad OTH exome AF: 0.0601

GnomAD4 exome AF: 0.0848 AC: 124012 AN: 1461808 Hom.: 5998 Cov.: 32 AF XY: 0.0841 AC XY: 61166 AN XY: 727198

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.0294

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0547

Gnomad4 FIN exome AF: 0.0597

Gnomad4 NFE exome AF: 0.0959

Gnomad4 OTH exome AF: 0.0784

GnomAD4 genome AF: 0.0560 AC: 8526 AN: 152364 Hom.: 310 Cov.: 33 AF XY: 0.0537 AC XY: 3998 AN XY: 74514

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0315

Gnomad4 ASJ AF: 0.0997

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0499

Gnomad4 FIN AF: 0.0578

Gnomad4 NFE AF: 0.0891

Gnomad4 OTH AF: 0.0406

Alfa AF: 0.0798 Hom.: 279

Bravo AF: 0.0530

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0857

EpiControl AF: 0.0839

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lipoic acid synthetase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35086467; hg19: chr4-39466779; COSMIC: COSV54695749; COSMIC: COSV54695749;