rs6037255

Positions:

• chr20-2658924-G-T

Variant summary

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

The NM_006899.5(IDH3B):​c.1072-87C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,587,328 control chromosomes in the GnomAD database, including 61,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7999 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53333 hom.)
• Consequence: IDH3B NM_006899.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06

Genes affected

IDH3B (HGNC:5385): (isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit beta) 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 beta subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 20-2658924-G-T is Benign according to our data. Variant chr20-2658924-G-T is described in ClinVar as [Benign]. Clinvar id is 1239037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3B	NM_006899.5	c.1072-87C>A		intron_variant		ENST00000380843.9	NP_008830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3B	ENST00000380843.9	c.1072-87C>A		intron_variant		1	NM_006899.5	ENSP00000370223

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47783 AN: 151880 Hom.: 7988 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.269 AC: 386455 AN: 1435328 Hom.: 53333 Cov.: 30 AF XY: 0.268 AC XY: 190858 AN XY: 712570

Gnomad4 AFR exome AF: 0.420

Gnomad4 AMR exome AF: 0.394

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.249

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.263

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.315 AC: 47839 AN: 152000 Hom.: 7999 Cov.: 32 AF XY: 0.313 AC XY: 23251 AN XY: 74300

Gnomad4 AFR AF: 0.414

Gnomad4 AMR AF: 0.369

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.305

Alfa AF: 0.277 Hom.: 10444

Bravo AF: 0.329

Asia WGS AF: 0.326 AC: 1134 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs6037255; hg19: chr20-2639570;