rs2259073

chr4-39473454-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006859.4(LIAS):c.1066+243A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 331,442 control chromosomes in the GnomAD database, including 4,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1662 hom., cov: 33)
  • Exomes 𝑓: 0.16 (2490 hom.)
• Consequence: LIAS NM_006859.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.257

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-39473454-A-C is Benign according to our data. Variant chr4-39473454-A-C is described in ClinVar as [Benign]. Clinvar id is 683063.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIAS	NM_006859.4	c.1066+243A>C		intron_variant		ENST00000640888.2
LIAS	NM_001278590.2	c.937+243A>C		intron_variant
LIAS	NM_001363700.2	c.757+243A>C		intron_variant
LIAS	NM_194451.3	c.954+2148A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIAS	ENST00000640888.2	c.1066+243A>C		intron_variant		1	NM_006859.4	P1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20757 AN: 152144 Hom.: 1660 Cov.: 33

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.163 AC: 29248 AN: 179180 Hom.: 2490 Cov.: 0 AF XY: 0.164 AC XY: 15070 AN XY: 91802

Gnomad4 AFR exome AF: 0.0735

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.136 AC: 20753 AN: 152262 Hom.: 1662 Cov.: 33 AF XY: 0.136 AC XY: 10104 AN XY: 74450

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.184

Alfa AF: 0.160 Hom.: 4254

Bravo AF: 0.141

Asia WGS AF: 0.166 AC: 579 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	11
Dann	Benign	0.83

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: rs2259073; hg19: chr4-39475074;