chrX-153786146-GGGCTACAGGA-G

Variant names:

• chrX-153786146-GGGCTACAGGA-G
• rs781829485
• NM_004135.4:c.1080+56_1080+65delTCCTGTAGCC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_174869.3(IDH3G):​c.1136_*2delTCCTGTAGCC​(p.Leu379fs) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000541 in 1,200,768 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.000054 (0 hom. 17 hem.)
• Consequence: IDH3G NM_174869.3 frameshift, stop_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.75
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM4: Stoplost variant in NM_174869.3
• BP6: Variant X-153786146-GGGCTACAGGA-G is Benign according to our data. Variant chrX-153786146-GGGCTACAGGA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2661732.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174869.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3G	NM_004135.4	MANE Select	c.1080+56_1080+65delTCCTGTAGCC		intron	N/A	NP_004126.1	P51553-1
	IDH3G	NM_174869.3		c.1136_*2delTCCTGTAGCC	p.Leu379fs	frameshift stop_lost	Exon 12 of 12	NP_777358.1	P51553-2
	IDH3G	NM_174869.3		c.1136_*2delTCCTGTAGCC		3_prime_UTR	Exon 12 of 12	NP_777358.1	P51553-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3G	ENST00000217901.10	TSL:1 MANE Select	c.1080+56_1080+65delTCCTGTAGCC		intron	N/A	ENSP00000217901.5	P51553-1
	IDH3G	ENST00000454076.5	TSL:1	c.495+56_495+65delTCCTGTAGCC		intron	N/A	ENSP00000400115.1	H0Y5Q7
	IDH3G	ENST00000370092.7	TSL:5	c.1136_*2delTCCTGTAGCC	p.Leu379fs	frameshift stop_lost	Exon 12 of 12	ENSP00000359110.3	P51553-2

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 6 AN: 112948 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000929

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000100 AC: 17 AN: 169615 AF XY: 0.000105

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000401

Gnomad OTH exome AF: 0.000961

GnomAD4 exome AF: 0.0000542 AC: 59 AN: 1087820 Hom.: 0 AF XY: 0.0000479 AC XY: 17 AN XY: 355188

African (AFR) AF: 0.000456 AC: 12 AN: 26290

American (AMR) AF: 0.000317 AC: 11 AN: 34675

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18711

East Asian (EAS) AF: 0.00 AC: 0 AN: 30053

South Asian (SAS) AF: 0.0000379 AC: 2 AN: 52727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39780

Middle Eastern (MID) AF: 0.00171 AC: 7 AN: 4095

European-Non Finnish (NFE) AF: 0.0000215 AC: 18 AN: 835854

Other (OTH) AF: 0.000197 AC: 9 AN: 45635

GnomAD4 genome AF: 0.0000531 AC: 6 AN: 112948 Hom.: 0 Cov.: 24 AF XY: 0.000114 AC XY: 4 AN XY: 35096

African (AFR) AF: 0.000129 AC: 4 AN: 31089

American (AMR) AF: 0.0000929 AC: 1 AN: 10765

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3616

South Asian (SAS) AF: 0.00 AC: 0 AN: 2802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53305

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=173/27	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs781829485; hg19: chrX-153051601;