X-153794101-G-A

Position:

• chrX-153794101-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004135.4(IDH3G):​c.81+145C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 611,213 control chromosomes in the GnomAD database, including 21,019 homozygotes. There are 53,479 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (3285 hom., 9567 hem., cov: 25)
  • Exomes 𝑓: 0.30 (17734 hom. 43912 hem.)
• Consequence: IDH3G NM_004135.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.276

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]

SSR4 (HGNC:11326): (signal sequence receptor subunit 4) This gene encodes the delta subunit of the translocon-associated protein complex which is involved in translocating proteins across the endoplasmic reticulum membrane. The encoded protein is located in the Xq28 region and is arranged in a compact head-to-head manner with the isocitrate dehydrogenase 3 (NAD+) gamma gene and both genes are driven by a CpG-embedded bidirectional promoter. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-153794101-G-A is Benign according to our data. Variant chrX-153794101-G-A is described in ClinVar as [Benign]. Clinvar id is 1258271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDH3G	NM_004135.4	c.81+145C>T		intron_variant		ENST00000217901.10	NP_004126.1
IDH3G	NM_174869.3	c.81+145C>T		intron_variant			NP_777358.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDH3G	ENST00000217901.10	c.81+145C>T		intron_variant		1	NM_004135.4	ENSP00000217901	P1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 29705 AN: 112257 Hom.: 3283 Cov.: 25 AF XY: 0.278 AC XY: 9563 AN XY: 34445

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.426

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.292

GnomAD4 exome AF: 0.300 AC: 149487 AN: 498907 Hom.: 17734 Cov.: 7 AF XY: 0.339 AC XY: 43912 AN XY: 129365

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.482

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.634

Gnomad4 SAS exome AF: 0.566

Gnomad4 FIN exome AF: 0.320

Gnomad4 NFE exome AF: 0.254

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.264 AC: 29702 AN: 112306 Hom.: 3285 Cov.: 25 AF XY: 0.277 AC XY: 9567 AN XY: 34504

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.326

Gnomad4 EAS AF: 0.638

Gnomad4 SAS AF: 0.578

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.298

Alfa AF: 0.284 Hom.: 8706

Bravo AF: 0.270

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2071125; hg19: chrX-153059556;