15-78168983-G-A

Variant summary

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

The NM_005530.3(IDH3A):c.1079G>A(p.Arg360His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,446,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: IDH3A NM_005530.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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]

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=0.14028224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH3A	NM_005530.3	c.1079G>A	p.Arg360His	missense_variant	11/11	ENST00000299518.7
ACSBG1	NM_015162.5	c.*2461C>T		3_prime_UTR_variant	14/14	ENST00000258873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH3A	ENST00000299518.7	c.1079G>A	p.Arg360His	missense_variant	11/11	1	NM_005530.3	P1
ACSBG1	ENST00000258873.9	c.*2461C>T		3_prime_UTR_variant	14/14	1	NM_015162.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250716 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1446972 Hom.: 0 Cov.: 27 AF XY: 0.0000181 AC XY: 13 AN XY: 718314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000898

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000109

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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

Invitae

Feb 04, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 360 of the IDH3A protein (p.Arg360His). This variant is present in population databases (rs769406487, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with IDH3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1041031). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.049
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.0010	B;.;.
Vest4		0.13
MVP		0.58
MPC		1.1
ClinPred		0.20	T
GERP RS		2.2
Varity_R		0.13
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769406487; hg19: chr15-78461325;