rs761295906

Variant names:

• chr4-39460866-A-C
• NM_006859.4:c.122A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-39460866-A-C
• chr4-39460866-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006859.4(LIAS):​c.122A>C​(p.Asn41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIAS NM_006859.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09635913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4	c.122A>C	p.Asn41Thr	missense_variant	Exon 2 of 11	ENST00000640888.2	NP_006850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2	c.122A>C	p.Asn41Thr	missense_variant	Exon 2 of 11	1	NM_006859.4	ENSP00000492260.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460950 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.45	T;T;T;.;T;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.096	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.22	N;.;.;N;.;.;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	.;.;.;N;N;N;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.42	.;.;.;T;T;T;T;.;.
Sift4G	Benign	0.52	.;.;.;T;T;T;T;.;.
Polyphen		0.0	B;B;B;.;B;.;.;.;.
Vest4		0.28, 0.30, 0.29, 0.30
MutPred		0.19		Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);Loss of catalytic residue at N41 (P = 0.0626);
MVP		0.66
MPC		0.39
ClinPred		0.72	D
GERP RS		4.9
Varity_R		0.10
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-39462486;