15-78168952-A-G

Position:

• chr15-78168952-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005530.3(IDH3A):​c.1048A>G​(p.Lys350Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,451,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IDH3A NM_005530.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

Genes affected

IDH3A (HGNC:5384): (isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. [provided by RefSeq, Jul 2008]

ACSBG1 (HGNC:29567): (acyl-CoA synthetase bubblegum family member 1) The protein encoded by this gene possesses long-chain acyl-CoA synthetase activity. It is thought to play a central role in brain very long-chain fatty acids metabolism and myelinogenesis. [provided by RefSeq, Jul 2008]

IDH3A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue N6-succinyllysine (size 0) in uniprot entity IDH3A_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3A	NM_005530.3	c.1048A>G	p.Lys350Glu	missense_variant	11/11	ENST00000299518.7	NP_005521.1
ACSBG1	NM_015162.5	c.*2492T>C		3_prime_UTR_variant	14/14	ENST00000258873.9	NP_055977.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3A	ENST00000299518.7	c.1048A>G	p.Lys350Glu	missense_variant	11/11	1	NM_005530.3	ENSP00000299518.2
ACSBG1	ENST00000258873	c.*2492T>C		3_prime_UTR_variant	14/14	1	NM_015162.5	ENSP00000258873.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451848 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721146

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with IDH3A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamic acid at codon 350 of the IDH3A protein (p.Lys350Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.083	T;D;D
Sift4G	Uncertain	0.056	T;D;T
Polyphen		0.14	B;.;.
Vest4		0.46
MutPred		0.52		Loss of ubiquitination at K350 (P = 0.013);.;.;
MVP		0.81
MPC		2.0
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.67
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr15-78461294;