rs201574806

Positions:

• chr4-39463613-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000424936.6(LIAS):​c.401C>A​(p.Pro134Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,610,268 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P134A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: LIAS ENST00000424936.6 missense
• Scores: Splicing: ADA: 0.0001493
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002739668).
• BP6: Variant 4-39463613-C-A is Benign according to our data. Variant chr4-39463613-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 206036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00143 (218/152284) while in subpopulation NFE AF= 0.00248 (169/68034). AF 95% confidence interval is 0.00218. There are 1 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIAS	NM_006859.4	c.393+8C>A		splice_region_variant, intron_variant		ENST00000640888.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIAS	ENST00000640888.2	c.393+8C>A		splice_region_variant, intron_variant		1	NM_006859.4	P1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00138 AC: 344 AN: 248812 Hom.: 2 AF XY: 0.00141 AC XY: 190 AN XY: 134568

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000594

Gnomad ASJ exome AF: 0.00508

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00111 AC: 1613 AN: 1457984 Hom.: 8 Cov.: 31 AF XY: 0.00117 AC XY: 847 AN XY: 725122

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00575

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00216

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74466

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00268 Hom.: 0

Bravo AF: 0.000793

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00173 AC: 210

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lipoic acid synthetase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

LIAS: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.4
DANN	Benign	0.72
DEOGEN2	Benign	0.053	T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0027	T
MutationTaster	Benign	1.0	D;D;D;N
Polyphen		0.0	B
GERP RS		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.014
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: rs201574806; hg19: chr4-39465233;