15-78149429-A-G

Position:

chr15-78149429-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005530.3(IDH3A):c.26A>G(p.Lys9Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000079 in 1,392,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

IDH3A
NM_005530.3 missense, splice_region

Scores

Splicing: ADA: 0.9376

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.891

Variant links:

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]

IDH3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11039108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3A	NM_005530.3 linkuse as main transcript	c.26A>G	p.Lys9Arg	missense_variant, splice_region_variant	1/11	ENST00000299518.7	NP_005521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3A	ENST00000299518.7 linkuse as main transcript	c.26A>G	p.Lys9Arg	missense_variant, splice_region_variant	1/11	1	NM_005530.3	ENSP00000299518	P1	P50213-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000570

AC:

AN:

157846

Hom.:

AF XY:

0.0000113

AC XY:

AN XY:

88204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000731

GnomAD4 exome

AF:

0.00000790

AC:

AN:

1392908

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

690584

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000208

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:

9.22e-7

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000344

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.26A>G (p.K9R) alteration is located in exon 1 (coding exon 1) of the IDH3A gene. This alteration results from a A to G substitution at nucleotide position 26, causing the lysine (K) at amino acid position 9 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 9 of the IDH3A protein (p.Lys9Arg). This variant is present in population databases (rs754172541, gnomAD 0.02%). 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: 1346201). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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

0.077

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.31

T;T;T;T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.42

T;T;T;T;T

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.093

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.;.;.

MutationTaster

Benign

0.93

D;D;D;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.29

N;N;N;N;.

REVEL

Benign

0.10

Sift

Benign

0.52

T;T;T;D;.

Sift4G

Benign

0.55

T;T;T;D;D

Polyphen

0.0

B;.;.;.;.

Vest4

0.11

MutPred

0.35

Loss of methylation at K9 (P = 0.0436);Loss of methylation at K9 (P = 0.0436);Loss of methylation at K9 (P = 0.0436);Loss of methylation at K9 (P = 0.0436);Loss of methylation at K9 (P = 0.0436);

MVP

0.61

MPC

0.72

ClinPred

0.056

GERP RS

4.3

Varity_R

0.061

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.75

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over