rs371053949

Variant names:

• chr4-39467635-G-A
• rs371053949
• NM_006859.4:c.726G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_006859.4(LIAS):​c.726G>A​(p.Pro242Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000095 in 1,579,178 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (2 hom.)
• Consequence: LIAS NM_006859.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.785

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-39467635-G-A is Benign according to our data. Variant chr4-39467635-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.785 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152260) while in subpopulation EAS AF= 0.00289 (15/5196). AF 95% confidence interval is 0.00178. There are 1 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4	c.726G>A	p.Pro242Pro	synonymous_variant	Exon 7 of 11	ENST00000640888.2	NP_006850.2
LIAS	NM_194451.3	c.726G>A	p.Pro242Pro	synonymous_variant	Exon 7 of 10		NP_919433.1
LIAS	NM_001363700.2	c.417G>A	p.Pro139Pro	synonymous_variant	Exon 4 of 8		NP_001350629.1
LIAS	NM_001278590.2	c.608+2293G>A		intron_variant	Intron 6 of 9		NP_001265519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.726G>A	p.Pro242Pro	synonymous_variant	Exon 7 of 11	1	NM_006859.4	ENSP00000492260.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000225 AC: 53 AN: 235228 Hom.: 1 AF XY: 0.000195 AC XY: 25 AN XY: 127968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000342

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00261

Gnomad SAS exome AF: 0.0000366

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.000534

GnomAD4 exome AF: 0.0000883 AC: 126 AN: 1426918 Hom.: 2 Cov.: 30 AF XY: 0.0000648 AC XY: 46 AN XY: 710192

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.0000250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000110

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74432

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000174

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lipoic acid synthetase deficiency Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 25, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LIAS-related disorder Benign:1

Jun 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.2
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs371053949; hg19: chr4-39469255;