NM_006859.4:c.306C>A

Variant names:

• chr4-39462283-C-A
• rs61731032
• NM_006859.4:c.306C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006859.4(LIAS):​c.306C>A​(p.Leu102Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,515,042 control chromosomes in the GnomAD database, including 1,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (105 hom., cov: 33)
  • Exomes 𝑓: 0.031 (940 hom.)
• Consequence: LIAS NM_006859.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.119
• Publications: 4 publications found

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]

LIAS Gene-Disease associations (from GenCC):

• lipoic acid synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 4-39462283-C-A is Benign according to our data. Variant chr4-39462283-C-A is described in ClinVar as Benign. ClinVar VariationId is 138118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0852 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	NM_006859.4	MANE Select	c.306C>A	p.Leu102Leu	synonymous	Exon 3 of 11	NP_006850.2
	LIAS	NM_001278590.2		c.306C>A	p.Leu102Leu	synonymous	Exon 3 of 10	NP_001265519.1	O43766-3
	LIAS	NM_194451.3		c.306C>A	p.Leu102Leu	synonymous	Exon 3 of 10	NP_919433.1	O43766-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	ENST00000640888.2	TSL:1 MANE Select	c.306C>A	p.Leu102Leu	synonymous	Exon 3 of 11	ENSP00000492260.1	O43766-1
	LIAS	ENST00000424936.6	TSL:1	c.306C>A	p.Leu102Leu	synonymous	Exon 3 of 4	ENSP00000491086.1	Q6P5Q6
	LIAS	ENST00000946185.1		c.300C>A	p.Leu100Leu	synonymous	Exon 3 of 11	ENSP00000616244.1

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4205 AN: 152060 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.00715

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.00908

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0367 AC: 7632 AN: 208012 AF XY: 0.0377

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0325

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0849

Gnomad FIN exome AF: 0.00904

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0579

GnomAD4 exome AF: 0.0313 AC: 42637 AN: 1362864 Hom.: 940 Cov.: 21 AF XY: 0.0317 AC XY: 21567 AN XY: 679766

African (AFR) AF: 0.00726 AC: 212 AN: 29202

American (AMR) AF: 0.0347 AC: 1237 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.0996 AC: 2448 AN: 24568

East Asian (EAS) AF: 0.103 AC: 3530 AN: 34420

South Asian (SAS) AF: 0.0334 AC: 2518 AN: 75396

European-Finnish (FIN) AF: 0.0109 AC: 565 AN: 52020

Middle Eastern (MID) AF: 0.101 AC: 542 AN: 5382

European-Non Finnish (NFE) AF: 0.0278 AC: 29217 AN: 1049922

Other (OTH) AF: 0.0420 AC: 2368 AN: 56334

GnomAD4 genome AF: 0.0277 AC: 4214 AN: 152178 Hom.: 105 Cov.: 33 AF XY: 0.0275 AC XY: 2047 AN XY: 74396

African (AFR) AF: 0.00713 AC: 296 AN: 41536

American (AMR) AF: 0.0434 AC: 664 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3468

East Asian (EAS) AF: 0.0920 AC: 476 AN: 5174

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4828

European-Finnish (FIN) AF: 0.00908 AC: 96 AN: 10572

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0293 AC: 1994 AN: 67994

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0334 Hom.: 82

Bravo AF: 0.0306

Asia WGS AF: 0.0700 AC: 242 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Lipoic acid synthetase deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.4
DANN	Benign	0.78
PhyloP100		-0.12
PromoterAI		-0.0020	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61731032; hg19: chr4-39463903; COSMIC: COSV54695742; COSMIC: COSV54695742;