15-78168982-C-T

Position:

chr15-78168982-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_005530.3(IDH3A):c.1078C>T(p.Arg360Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,598,718 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 29 hom. )

Consequence

IDH3A
NM_005530.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.50

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:

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]

ACSBG1 links:

IDH3A (HGNC:):

IDH3A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011196941).

BP6

Variant 15-78168982-C-T is Benign according to our data. Variant chr15-78168982-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1146800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3A	NM_005530.3 linkuse as main transcript	c.1078C>T	p.Arg360Cys	missense_variant	11/11	ENST00000299518.7	NP_005521.1	P50213-1
ACSBG1	NM_015162.5 linkuse as main transcript	c.*2462G>A		3_prime_UTR_variant	14/14	ENST00000258873.9	NP_055977.3	Q96GR2B3KNS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3A	ENST00000299518.7 linkuse as main transcript	c.1078C>T	p.Arg360Cys	missense_variant	11/11	1	NM_005530.3	ENSP00000299518.2		P50213-1
ACSBG1	ENST00000258873 linkuse as main transcript	c.*2462G>A		3_prime_UTR_variant	14/14	1	NM_015162.5	ENSP00000258873.4		Q96GR2

Frequencies

GnomAD3 genomes

AF:

0.00267

AC:

407

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00465

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00232

AC:

582

AN:

250668

Hom.:

AF XY:

0.00228

AC XY:

309

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000230

Gnomad FIN exome

AF:

0.000648

Gnomad NFE exome

AF:

0.00402

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00438

AC:

6342

AN:

1446430

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

3035

AN XY:

717988

show subpopulations

Gnomad4 AFR exome

AF:

0.000540

Gnomad4 AMR exome

AF:

0.00182

Gnomad4 ASJ exome

AF:

0.00177

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000246

Gnomad4 FIN exome

AF:

0.000884

Gnomad4 NFE exome

AF:

0.00530

Gnomad4 OTH exome

AF:

0.00459

GnomAD4 genome

AF:

0.00267

AC:

407

AN:

152288

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00465

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00416

Hom.:

Bravo

AF:

0.00284

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00559

AC:

ExAC

AF:

0.00219

AC:

266

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

IDH3A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.7

M;.;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.45

B;.;.

Vest4

0.40

MVP

0.75

MPC

1.4

ClinPred

0.040

GERP RS

5.3

Varity_R

0.24

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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