X-153787071-C-T

Variant names:

• chrX-153787071-C-T
• rs1188987247
• NM_004135.4:c.757G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004135.4(IDH3G):​c.757G>A​(p.Val253Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 112,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 25)
• Consequence: IDH3G NM_004135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH3G	NM_004135.4	c.757G>A	p.Val253Met	missense_variant	Exon 9 of 13	ENST00000217901.10	NP_004126.1
IDH3G	NM_174869.3	c.757G>A	p.Val253Met	missense_variant	Exon 9 of 12		NP_777358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH3G	ENST00000217901.10	c.757G>A	p.Val253Met	missense_variant	Exon 9 of 13	1	NM_004135.4	ENSP00000217901.5

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112798 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34942

Gnomad AFR AF: 0.0000644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112798 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34942

Gnomad4 AFR AF: 0.0000644

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.757G>A (p.V253M) alteration is located in exon 9 (coding exon 9) of the IDH3G gene. This alteration results from a G to A substitution at nucleotide position 757, causing the valine (V) at amino acid position 253 to be replaced by a methionine (M). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;D;.;D;D;D;D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N;N;N;N;.;N;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;T
Polyphen		1.0	.;D;.;.;.;.;.
Vest4		0.58
MutPred		0.77		Loss of catalytic residue at V253 (P = 0.0031);Loss of catalytic residue at V253 (P = 0.0031);Loss of catalytic residue at V253 (P = 0.0031);.;.;.;.;
MVP		0.91
MPC		2.1
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.97

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: rs1188987247; hg19: chrX-153052526;