dbSNP rs372288500: LIAS:p.Ser2Cys (chr4-39459122-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_006859.4(LIAS):c.5C>G(p.Ser2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LIAS
NM_006859.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

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 links:

RPL9 (HGNC:10369): (ribosomal protein L9) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L6P family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

RPL9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIAS	NM_006859.4 link	c.5C>G	p.Ser2Cys	missense_variant	Exon 1 of 11	ENST00000640888.2	NP_006850.2	O43766-1A0A024R9W0
RPL9	NM_000661.5 link	c.-233G>C		upstream_gene_variant		ENST00000295955.14	NP_000652.2	P32969Q53Z07

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIAS	ENST00000640888.2 link	c.5C>G	p.Ser2Cys	missense_variant	Exon 1 of 11	1	NM_006859.4	ENSP00000492260.1		O43766-1
RPL9	ENST00000295955.14 link	c.-233G>C		upstream_gene_variant		1	NM_000661.5	ENSP00000346022.7		P32969

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727192

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Lipoic acid synthetase deficiency

Uncertain:1

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.070

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T;T;.;T;.;.;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.81

T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.5

L;.;.;L;.;.;L;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.0

.;.;.;N;N;N;N;.;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.010

.;.;.;D;D;D;D;.;.

Sift4G

Uncertain

0.044

.;.;.;D;T;T;T;.;.

Polyphen

0.38

B;D;P;.;B;.;.;.;.

Vest4

0.50, 0.53, 0.49, 0.49

MutPred

0.35

Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);Loss of phosphorylation at S2 (P = 0.0376);

MVP

0.88

MPC

0.48

ClinPred

0.95

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.27

gMVP

0.48

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over