chr20-2658516-T-C

Position:

• chr20-2658516-T-C

Variant summary

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

The NM_001330763.2(IDH3B):​c.1157A>G​(p.Asn386Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0104 in 1,613,486 control chromosomes in the GnomAD database, including 1,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (726 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (647 hom.)
• Consequence: IDH3B NM_001330763.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.83

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 (MetaRNN=0.0015983284).
• BP6: Variant 20-2658516-T-C is Benign according to our data. Variant chr20-2658516-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 338008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3B	NM_006899.5	c.*235A>G		3_prime_UTR_variant	12/12	ENST00000380843.9	NP_008830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3B	ENST00000474315.5	c.1157A>G	p.Asn386Ser	missense_variant	13/13	1		ENSP00000482773.1
IDH3B	ENST00000380843.9	c.*235A>G		3_prime_UTR_variant	12/12	1	NM_006899.5	ENSP00000370223.4

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8194 AN: 151630 Hom.: 725 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000942

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0146 AC: 3665 AN: 250816 Hom.: 284 AF XY: 0.0104 AC XY: 1406 AN XY: 135586

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000688

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000846

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.00591 AC: 8639 AN: 1461738 Hom.: 647 Cov.: 34 AF XY: 0.00517 AC XY: 3757 AN XY: 727154

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000650

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000576

Gnomad4 OTH exome AF: 0.0132

GnomAD4 genome AF: 0.0540 AC: 8200 AN: 151748 Hom.: 726 Cov.: 32 AF XY: 0.0520 AC XY: 3856 AN XY: 74170

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.0219

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000942

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.00961 Hom.: 183

Bravo AF: 0.0603

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.180 AC: 794

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0179 AC: 2167

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0016	T
Sift4G	Benign	0.21	T
Vest4		0.10
ClinPred		0.10	T
GERP RS		5.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
gMVP		0.50

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: rs8296; hg19: chr20-2639162;