X-153790253-T-C

Variant names:

• chrX-153790253-T-C
• rs1403014875
• NM_004135.4:c.175A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004135.4(IDH3G):​c.175A>G​(p.Met59Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,097,434 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. 12/20 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: 0.000028 (0 hom. 8 hem.)
• Consequence: IDH3G NM_004135.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH3G	NM_004135.4	c.175A>G	p.Met59Val	missense_variant	Exon 4 of 13	ENST00000217901.10	NP_004126.1
IDH3G	NM_174869.3	c.175A>G	p.Met59Val	missense_variant	Exon 4 of 12		NP_777358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH3G	ENST00000217901.10	c.175A>G	p.Met59Val	missense_variant	Exon 4 of 13	1	NM_004135.4	ENSP00000217901.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.0000282 AC: 31 AN: 1097434 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 8 AN XY: 362958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175A>G (p.M59V) alteration is located in exon 4 (coding exon 4) of the IDH3G gene. This alteration results from a A to G substitution at nucleotide position 175, causing the methionine (M) at amino acid position 59 to be replaced by a valine (V). 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	0.18
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	.;D;.;T;T;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.35	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.15	N;N;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N;N;N;.;N
REVEL	Benign	0.26
Sift	Benign	0.058	T;T;T;T;.;T
Sift4G	Benign	0.075	T;D;T;T;T;T
Polyphen		0.32	.;B;.;.;.;.
Vest4		0.61
MutPred		0.51		Loss of methylation at R54 (P = 0.1345);Loss of methylation at R54 (P = 0.1345);Loss of methylation at R54 (P = 0.1345);.;.;.;
MVP		0.70
MPC		1.5
ClinPred		0.80	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.87

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: rs1403014875; hg19: chrX-153055708;