rs11630776

Variant names:

• chr15-78155448-C-G
• rs11630776
• NM_005530.3:c.90+173C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005530.3(IDH3A):​c.90+173C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 475,528 control chromosomes in the GnomAD database, including 24,016 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6432 hom., cov: 33)
  • Exomes 𝑓: 0.31 (17584 hom.)
• Consequence: IDH3A NM_005530.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.777
• Publications: 6 publications found

Genes affected

IDH3A (HGNC:5384): (isocitrate dehydrogenase (NAD(+)) 3 catalytic subunit alpha) 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 alpha subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. [provided by RefSeq, Jul 2008]

IDH3A Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AR Classification: STRONG Submitted by: G2P
• retinitis pigmentosa 90

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-78155448-C-G is Benign according to our data. Variant chr15-78155448-C-G is described in ClinVar as Benign. ClinVar VariationId is 1280196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005530.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3A	NM_005530.3	MANE Select	c.90+173C>G		intron	N/A	NP_005521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3A	ENST00000299518.7	TSL:1 MANE Select	c.90+173C>G		intron	N/A	ENSP00000299518.2
	IDH3A	ENST00000559889.5	TSL:1	n.116+173C>G		intron	N/A
	IDH3A	ENST00000560414.1	TSL:2	n.275C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40585 AN: 152002 Hom.: 6428 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.311 AC: 100540 AN: 323408 Hom.: 17584 Cov.: 4 AF XY: 0.310 AC XY: 52974 AN XY: 170810

African (AFR) AF: 0.105 AC: 961 AN: 9122

American (AMR) AF: 0.244 AC: 2715 AN: 11146

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 3638 AN: 10652

East Asian (EAS) AF: 0.0288 AC: 726 AN: 25194

South Asian (SAS) AF: 0.242 AC: 5549 AN: 22922

European-Finnish (FIN) AF: 0.325 AC: 7841 AN: 24106

Middle Eastern (MID) AF: 0.327 AC: 499 AN: 1524

European-Non Finnish (NFE) AF: 0.365 AC: 72712 AN: 199454

Other (OTH) AF: 0.306 AC: 5899 AN: 19288

GnomAD4 genome AF: 0.267 AC: 40595 AN: 152120 Hom.: 6432 Cov.: 33 AF XY: 0.262 AC XY: 19452 AN XY: 74352

African (AFR) AF: 0.113 AC: 4668 AN: 41486

American (AMR) AF: 0.268 AC: 4096 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3470

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5192

South Asian (SAS) AF: 0.227 AC: 1095 AN: 4820

European-Finnish (FIN) AF: 0.317 AC: 3346 AN: 10564

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24906 AN: 67982

Other (OTH) AF: 0.278 AC: 588 AN: 2114

Alfa AF: 0.308 Hom.: 988

Bravo AF: 0.256

Asia WGS AF: 0.132 AC: 460 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.94
DANN	Benign	0.31
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11630776; hg19: chr15-78447790;