Genetic Variant ENST00000424936.6:c.401C>A (chr4-39463613-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 10/11 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:3

Conservation

PhyloP100: 0.00

Publications

0 publications found

Variant links:

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LIAS links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000424936.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIAS	NM_006859.4	MANE Select	c.393+8C>A		splice_region intron	N/A	NP_006850.2
LIAS	NM_001278591.2		c.401C>A	p.Pro134Gln	missense	Exon 4 of 4	NP_001265520.1	Q6P5Q6
LIAS	NM_001278592.2		c.*4C>A		3_prime_UTR	Exon 3 of 3	NP_001265521.1	B4E0L7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIAS	ENST00000424936.6	TSL:1	c.401C>A	p.Pro134Gln	missense	Exon 4 of 4	ENSP00000491086.1	Q6P5Q6
LIAS	ENST00000640888.2	TSL:1 MANE Select	c.393+8C>A		splice_region intron	N/A	ENSP00000492260.1	O43766-1
LIAS	ENST00000509519.5	TSL:2	c.*4C>A		3_prime_UTR	Exon 3 of 3	ENSP00000492833.1	B4E0L7

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152166

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00138

AC:

344

AN:

248812

AF XY:

0.00141

show subpopulations

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 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.:

Cov.:

AF XY:

0.00117

AC XY:

847

AN XY:

725122

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33356

American (AMR)

AF:

0.000112

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.00575

AC:

150

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85704

European-Finnish (FIN)

AF:

0.00216

AC:

115

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00113

AC:

1257

AN:

1109562

Other (OTH)

AF:

0.00138

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00143

AC:

218

AN:

152284

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41554

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00248

AC:

169

AN:

68034

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.000793

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Lipoic acid synthetase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.4

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.053

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0027

PhyloP100

0.0

Mutation Taster

=100/0

polymorphism

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over