X-153786822-A-C

Position:

• chrX-153786822-A-C

Variant summary

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

The NM_004135.4(IDH3G):​c.903T>G​(p.His301Gln) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: IDH3G NM_004135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.29

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]

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.903T>G	p.His301Gln	missense_variant	10/13	ENST00000217901.10	NP_004126.1
IDH3G	NM_174869.3	c.903T>G	p.His301Gln	missense_variant	10/12		NP_777358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3G	ENST00000217901.10	c.903T>G	p.His301Gln	missense_variant	10/13	1	NM_004135.4	ENSP00000217901.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.13e-7 AC: 1 AN: 1094896 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 1 AN XY: 361082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jul 27, 2022

The c.903T>G (p.H301Q) alteration is located in exon 10 (coding exon 10) of the IDH3G gene. This alteration results from a T to G substitution at nucleotide position 903, causing the histidine (H) at amino acid position 301 to be replaced by a glutamine (Q). 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	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.63
DANN	Benign	0.76
DEOGEN2	Benign	0.36	.;T;.;T;T;T
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.60	T;T;T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.31	N;N;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.16	N;N;N;N;.;N
REVEL	Benign	0.077
Sift	Benign	0.35	T;T;T;T;.;T
Sift4G	Benign	0.55	T;T;T;T;T;T
Polyphen		0.049	.;B;.;.;.;.
Vest4		0.13
MutPred		0.38		Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);.;.;.;
MVP		0.25
MPC		0.96
ClinPred		0.35	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: 0

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-153052277;