chrX-153787885-C-A

Position:

• chrX-153787885-C-A

Variant summary

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

The NM_004135.4(IDH3G):​c.478G>T​(p.Asp160Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 25)
• Consequence: IDH3G NM_004135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.203

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3G	NM_004135.4	c.478G>T	p.Asp160Tyr	missense_variant	7/13	ENST00000217901.10	NP_004126.1
IDH3G	NM_174869.3	c.478G>T	p.Asp160Tyr	missense_variant	7/12		NP_777358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3G	ENST00000217901.10	c.478G>T	p.Asp160Tyr	missense_variant	7/13	1	NM_004135.4	ENSP00000217901.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.478G>T (p.D160Y) alteration is located in exon 7 (coding exon 7) of the IDH3G gene. This alteration results from a G to T substitution at nucleotide position 478, causing the aspartic acid (D) at amino acid position 160 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;D;D;D;D
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;.;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;D;D;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;.;.
Vest4		0.56
MutPred		0.53		Loss of catalytic residue at D160 (P = 0.0704);Loss of catalytic residue at D160 (P = 0.0704);Loss of catalytic residue at D160 (P = 0.0704);.;.;.;.;
MVP		0.68
MPC		2.2
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153053340;