4-39460917-C-T

Variant names:

• chr4-39460917-C-T
• rs141723499
• NM_006859.4:c.173C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_006859.4(LIAS):​c.173C>T​(p.Thr58Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,611,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T58N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LIAS NM_006859.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 0.0970
• Publications: 3 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

ENSG00000298395 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.073010445).
• BP6: Variant 4-39460917-C-T is Benign according to our data. Variant chr4-39460917-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540086.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	NM_006859.4	MANE Select	c.173C>T	p.Thr58Ile	missense	Exon 2 of 11	NP_006850.2
	LIAS	NM_001278590.2		c.173C>T	p.Thr58Ile	missense	Exon 2 of 10	NP_001265519.1
	LIAS	NM_194451.3		c.173C>T	p.Thr58Ile	missense	Exon 2 of 10	NP_919433.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	ENST00000640888.2	TSL:1 MANE Select	c.173C>T	p.Thr58Ile	missense	Exon 2 of 11	ENSP00000492260.1
	LIAS	ENST00000424936.6	TSL:1	c.173C>T	p.Thr58Ile	missense	Exon 2 of 4	ENSP00000491086.1
	LIAS	ENST00000381846.2	TSL:3	c.173C>T	p.Thr58Ile	missense	Exon 2 of 10	ENSP00000371270.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151992 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 250006 AF XY: 0.000111

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1459750 Hom.: 0 Cov.: 30 AF XY: 0.000161 AC XY: 117 AN XY: 726140

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.000135 AC: 6 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85750

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53306

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.000206 AC: 229 AN: 1111060

Other (OTH) AF: 0.0000829 AC: 5 AN: 60298

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151992 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74228

African (AFR) AF: 0.000121 AC: 5 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000231 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lipoic acid synthetase deficiency Uncertain:2 Other:1

Jul 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 07-21-2022 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the LIAS protein (p.Thr58Ile). This variant is present in population databases (rs141723499, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LIAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 540086). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases Benign:1

Mar 26, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.097
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.075
Sift	Benign	0.22	T
Sift4G	Benign	0.23	T
Polyphen		0.0040	B
Vest4		0.38
MVP		0.79
MPC		0.42
ClinPred		0.065	T
GERP RS		3.3
Varity_R		0.035
gMVP		0.36
Mutation Taster		=89/11	polymorphism

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: rs141723499; hg19: chr4-39462537;