15-78168982-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (29 hom.)
• Consequence: IDH3A NM_005530.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.50

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 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 GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDH3A	NM_005530.3	c.1078C>T	p.Arg360Cys	missense_variant	11/11	ENST00000299518.7
ACSBG1	NM_015162.5	c.*2462G>A		3_prime_UTR_variant	14/14	ENST00000258873.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDH3A	ENST00000299518.7	c.1078C>T	p.Arg360Cys	missense_variant	11/11	1	NM_005530.3	P1
ACSBG1	ENST00000258873.9	c.*2462G>A		3_prime_UTR_variant	14/14	1	NM_015162.5	P1

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 407 AN: 152170 Hom.: 2 Cov.: 33

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.: 2 AF XY: 0.00228 AC XY: 309 AN XY: 135534

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.: 29 Cov.: 28 AF XY: 0.00423 AC XY: 3035 AN XY: 717988

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.: 2 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74462

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.: 4

Bravo AF: 0.00284

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00559 AC: 48

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IDH3A-related disorder Benign:1

Likely benign, criteria provided, single submitter

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	25
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	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs116374996; hg19: chr15-78461324;