NM_004135.4:c.323G>A

Variant names:

• chrX-153789735-C-T
• NM_004135.4:c.323G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004135.4(IDH3G):​c.323G>A​(p.Arg108His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,086,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: IDH3G NM_004135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51
• Publications: 0 publications found

Genes affected

IDH3G (HGNC:5386): (isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma) 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 gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008]

IDH3G Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3G	NM_004135.4	MANE Select	c.323G>A	p.Arg108His	missense	Exon 5 of 13	NP_004126.1	P51553-1
	IDH3G	NM_174869.3		c.323G>A	p.Arg108His	missense	Exon 5 of 12	NP_777358.1	P51553-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3G	ENST00000217901.10	TSL:1 MANE Select	c.323G>A	p.Arg108His	missense	Exon 5 of 13	ENSP00000217901.5	P51553-1
	IDH3G	ENST00000958656.1		c.323G>A	p.Arg108His	missense	Exon 5 of 14	ENSP00000628715.1
	IDH3G	ENST00000958648.1		c.359G>A	p.Arg120His	missense	Exon 5 of 13	ENSP00000628707.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1086185 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 353509

African (AFR) AF: 0.00 AC: 0 AN: 26248

American (AMR) AF: 0.00 AC: 0 AN: 34356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19170

East Asian (EAS) AF: 0.00 AC: 0 AN: 29972

South Asian (SAS) AF: 0.00 AC: 0 AN: 52653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39845

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00000360 AC: 3 AN: 834155

Other (OTH) AF: 0.00 AC: 0 AN: 45666

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.54		Loss of sheet (P = 0.0063)
MVP		0.93
MPC		1.6
ClinPred		0.98	D
GERP RS		3.5
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.96
Mutation Taster		=52/48	polymorphism

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

Other links and lift over

hg19: chrX-153055190; COSMIC: COSV99473539; COSMIC: COSV99473539;