rs11630776

Positions:

• chr15-78155448-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005530.3(IDH3A):​c.90+173C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 475,528 control chromosomes in the GnomAD database, including 24,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6432 hom., cov: 33)
  • Exomes 𝑓: 0.31 (17584 hom.)
• Consequence: IDH3A NM_005530.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.777

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-78155448-C-G is Benign according to our data. Variant chr15-78155448-C-G is described in ClinVar as [Benign]. Clinvar id is 1280196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3A	NM_005530.3	c.90+173C>G		intron_variant		ENST00000299518.7	NP_005521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3A	ENST00000299518.7	c.90+173C>G		intron_variant		1	NM_005530.3	ENSP00000299518	P1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40585 AN: 152002 Hom.: 6428 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.311 AC: 100540 AN: 323408 Hom.: 17584 Cov.: 4 AF XY: 0.310 AC XY: 52974 AN XY: 170810

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.0288

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.325

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.267 AC: 40595 AN: 152120 Hom.: 6432 Cov.: 33 AF XY: 0.262 AC XY: 19452 AN XY: 74352

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.0322

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.278

Alfa AF: 0.308 Hom.: 988

Bravo AF: 0.256

Asia WGS AF: 0.132 AC: 460 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.94
DANN	Benign	0.31

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

Other links and lift over

dbSNP: rs11630776; hg19: chr15-78447790;