rs2259073

Variant names:

• chr4-39473454-A-C
• rs2259073
• NM_006859.4:c.1066+243A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-39473454-A-C
• chr4-39473454-A-G
• chr4-39473454-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LIAS	NM_006859.4	c.1066+243A>C		intron_variant	Intron 10 of 10	ENST00000640888.2	NP_006850.2
LIAS	NM_001278590.2	c.937+243A>C		intron_variant	Intron 9 of 9		NP_001265519.1
LIAS	NM_194451.3	c.954+2148A>C		intron_variant	Intron 9 of 9		NP_919433.1
LIAS	NM_001363700.2	c.757+243A>C		intron_variant	Intron 7 of 7		NP_001350629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.1066+243A>C		intron_variant	Intron 10 of 10	1	NM_006859.4	ENSP00000492260.1

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

African (AFR) AF: 0.0735 AC: 406 AN: 5524

American (AMR) AF: 0.201 AC: 1220 AN: 6082

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 1555 AN: 6888

East Asian (EAS) AF: 0.185 AC: 2754 AN: 14856

South Asian (SAS) AF: 0.159 AC: 963 AN: 6066

European-Finnish (FIN) AF: 0.142 AC: 1544 AN: 10898

Middle Eastern (MID) AF: 0.161 AC: 145 AN: 898

European-Non Finnish (NFE) AF: 0.160 AC: 18576 AN: 115868

Other (OTH) AF: 0.172 AC: 2085 AN: 12100

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

African (AFR) AF: 0.0670 AC: 2784 AN: 41572

American (AMR) AF: 0.198 AC: 3019 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3470

East Asian (EAS) AF: 0.177 AC: 918 AN: 5190

South Asian (SAS) AF: 0.162 AC: 780 AN: 4826

European-Finnish (FIN) AF: 0.129 AC: 1364 AN: 10604

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10555 AN: 68002

Other (OTH) AF: 0.184 AC: 389 AN: 2114

Alfa AF: 0.155 Hom.: 6043

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

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.26
Mutation Taster		=100/0	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: rs2259073; hg19: chr4-39475074;