Genetic Variant LIAS:p.Asp219Asp (chr4-39467566-T-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_006859.4(LIAS):c.657T>C(p.Asp219Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LIAS
NM_006859.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

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

LIAS links:

ENSG00000298383 (HGNC:):

ENSG00000298383 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP7

Synonymous conserved (PhyloP=1.11 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4 link	c.657T>C	p.Asp219Asp	synonymous_variant	Exon 7 of 11	ENST00000640888.2	NP_006850.2	O43766-1A0A024R9W0
LIAS	NM_194451.3 link	c.657T>C	p.Asp219Asp	synonymous_variant	Exon 7 of 10		NP_919433.1	O43766-2
LIAS	NM_001363700.2 link	c.348T>C	p.Asp116Asp	synonymous_variant	Exon 4 of 8		NP_001350629.1
LIAS	NM_001278590.2 link	c.608+2224T>C		intron_variant	Intron 6 of 9		NP_001265519.1	O43766-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.657T>C	p.Asp219Asp	synonymous_variant	Exon 7 of 11	1	NM_006859.4	ENSP00000492260.1		O43766-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456126

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724582

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33326

American (AMR)

AF:

0.00

AC:

AN:

43582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39394

South Asian (SAS)

AF:

0.00

AC:

AN:

85438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109278

Other (OTH)

AF:

0.00

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.5

(source)

DANN

Benign

0.63

PhyloP100

1.1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over