20-2658755-C-G

Position:

• chr20-2658755-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006899.5(IDH3B):​c.1154G>C​(p.Ser385Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDH3B NM_006899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.184

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08673605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3B	NM_006899.5	c.1154G>C	p.Ser385Thr	missense_variant	12/12	ENST00000380843.9	NP_008830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3B	ENST00000380843.9	c.1154G>C	p.Ser385Thr	missense_variant	12/12	1	NM_006899.5	ENSP00000370223.4
IDH3B	ENST00000474315.5	c.1150+4G>C		splice_region_variant, intron_variant		1		ENSP00000482773.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 10, 2020

This variant has not been reported in the literature in individuals with IDH3B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Not Available; PolyPhen-2: "Benign"; Align-GVGD: Not Available). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with threonine at codon 385 of the IDH3B protein (p.Ser385Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.057
Sift	Benign	0.051	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.12
MVP		0.30
MPC		0.35
ClinPred		0.95	D
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13

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: rs369372221; hg19: chr20-2639401;