rs2073192

Variant names:

• chr20-2664350-G-A
• rs2073192
• NR_186432.1:n.77G>A

Variant summary

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

The NR_186432.1(IDH3B-DT):​n.77G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0933 in 767,804 control chromosomes in the GnomAD database, including 4,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (656 hom., cov: 33)
  • Exomes 𝑓: 0.097 (3632 hom.)
• Consequence: IDH3B-DT NR_186432.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.478
• Publications: 8 publications found

Genes affected

IDH3B-DT (HGNC:55798): (IDH3B divergent transcript)

IDH3B (HGNC:5385): (isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit beta) 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 beta subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2016]

IDH3B Gene-Disease associations (from GenCC):

• retinitis pigmentosa 46

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• IDH3B-related retinopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-2664350-G-A is Benign according to our data. Variant chr20-2664350-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDH3B	NM_006899.5	c.-162C>T		upstream_gene_variant		ENST00000380843.9	NP_008830.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDH3B	ENST00000380843.9	c.-162C>T		upstream_gene_variant		1	NM_006899.5	ENSP00000370223.4
IDH3B	ENST00000474315.5	c.-162C>T		upstream_gene_variant		1		ENSP00000482773.1

Frequencies

GnomAD3 genomes AF: 0.0780 AC: 11862 AN: 152134 Hom.: 662 Cov.: 33

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0785

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0780

Gnomad OTH AF: 0.0827

GnomAD4 exome AF: 0.0971 AC: 59786 AN: 615552 Hom.: 3632 Cov.: 7 AF XY: 0.0980 AC XY: 32066 AN XY: 327326

African (AFR) AF: 0.0493 AC: 830 AN: 16844

American (AMR) AF: 0.168 AC: 5809 AN: 34586

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 820 AN: 20346

East Asian (EAS) AF: 0.231 AC: 7437 AN: 32170

South Asian (SAS) AF: 0.130 AC: 8299 AN: 63650

European-Finnish (FIN) AF: 0.0837 AC: 2887 AN: 34486

Middle Eastern (MID) AF: 0.0762 AC: 201 AN: 2638

European-Non Finnish (NFE) AF: 0.0803 AC: 30395 AN: 378410

Other (OTH) AF: 0.0959 AC: 3108 AN: 32422

GnomAD4 genome AF: 0.0779 AC: 11862 AN: 152252 Hom.: 656 Cov.: 33 AF XY: 0.0792 AC XY: 5897 AN XY: 74440

African (AFR) AF: 0.0490 AC: 2034 AN: 41550

American (AMR) AF: 0.0996 AC: 1524 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3470

East Asian (EAS) AF: 0.221 AC: 1143 AN: 5166

South Asian (SAS) AF: 0.142 AC: 686 AN: 4818

European-Finnish (FIN) AF: 0.0785 AC: 832 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0780 AC: 5307 AN: 68024

Other (OTH) AF: 0.0837 AC: 177 AN: 2114

Alfa AF: 0.0826 Hom.: 105

Bravo AF: 0.0815

Asia WGS AF: 0.203 AC: 705 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.3
DANN	Benign	0.83
PhyloP100		0.48
PromoterAI		-0.00030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2073192; hg19: chr20-2644996;