15-78149416-G-T

Position:

chr15-78149416-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005530.3(IDH3A):c.13G>T(p.Ala5Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,553,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

IDH3A
NM_005530.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.65

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06465089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH3A	NM_005530.3 linkuse as main transcript	c.13G>T	p.Ala5Ser	missense_variant	1/11	ENST00000299518.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH3A	ENST00000299518.7 linkuse as main transcript	c.13G>T	p.Ala5Ser	missense_variant	1/11	1	NM_005530.3	P1	P50213-1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000226

AC:

AN:

163608

Hom.:

AF XY:

0.000186

AC XY:

AN XY:

91162

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000718

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000322

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000627

Gnomad NFE exome

AF:

0.000324

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.000304

AC:

426

AN:

1401430

Hom.:

Cov.:

AF XY:

0.000302

AC XY:

210

AN XY:

695082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000504

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000843

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000528

Gnomad4 NFE exome

AF:

0.000353

Gnomad4 OTH exome

AF:

0.000275

GnomAD4 genome

AF:

0.000269

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000258

Hom.:

Bravo

AF:

0.000280

ESP6500AA

AF:

0.000238

AC:

ESP6500EA

AF:

0.000601

AC:

ExAC

AF:

0.000180

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

Oct 29, 2021

The c.13G>T (p.A5S) alteration is located in exon 1 (coding exon 1) of the IDH3A gene. This alteration results from a G to T substitution at nucleotide position 13, causing the alanine (A) at amino acid position 5 to be replaced by a serine (S). 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 17, 2022

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 5 of the IDH3A protein (p.Ala5Ser). This variant is present in population databases (rs199857658, gnomAD 0.05%). 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: 966798). 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

0.086

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;T;T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.57

T;T;T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.065

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.29

N;N;N;N;.

REVEL

Benign

0.074

Sift

Benign

0.084

T;T;T;D;.

Sift4G

Benign

0.24

T;T;T;T;D

Polyphen

0.18

B;.;.;.;.

Vest4

0.24

MVP

0.67

MPC

0.80

ClinPred

0.034

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.60

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

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