chr4-39463615-G-T

Variant names:

• chr4-39463615-G-T
• rs372094616
• ENST00000424936.6:c.403G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000424936.6(LIAS):​c.403G>T​(p.Ala135Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A135T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LIAS ENST00000424936.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08827868).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000424936.6. 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.393+10G>T		intron	N/A	NP_006850.2
	LIAS	NM_001278591.2		c.403G>T	p.Ala135Ser	missense	Exon 4 of 4	NP_001265520.1
	LIAS	NM_001278592.2		c.*6G>T		3_prime_UTR	Exon 3 of 3	NP_001265521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIAS	ENST00000424936.6	TSL:1	c.403G>T	p.Ala135Ser	missense	Exon 4 of 4	ENSP00000491086.1
	LIAS	ENST00000640888.2	TSL:1 MANE Select	c.393+10G>T		intron	N/A	ENSP00000492260.1
	LIAS	ENST00000509519.5	TSL:2	c.*6G>T		3_prime_UTR	Exon 3 of 3	ENSP00000492833.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248882 AF XY: 0.00

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457850 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724972

African (AFR) AF: 0.0000300 AC: 1 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 85702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109420

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.77
DEOGEN2	Benign	0.052	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.088	T
PhyloP100		0.11
Polyphen		0.069	B
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs372094616; hg19: chr4-39465235;