chr20-2658924-G-T

Variant names:

• chr20-2658924-G-T
• rs6037255
• NM_006899.5:c.1072-87C>A

Variant summary

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

The NM_006899.5(IDH3B):​c.1072-87C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,587,328 control chromosomes in the GnomAD database, including 61,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7999 hom., cov: 32)
  • Exomes 𝑓: 0.27 (53333 hom.)
• Consequence: IDH3B NM_006899.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.06
• Publications: 15 publications found

Genes affected

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=-0.91).
• BP6: Variant 20-2658924-G-T is Benign according to our data. Variant chr20-2658924-G-T is described in ClinVar as Benign. ClinVar VariationId is 1239037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006899.5. 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
	IDH3B	NM_006899.5	MANE Select	c.1072-87C>A		intron	N/A	NP_008830.2
	IDH3B	NM_001330763.2		c.1072-87C>A		intron	N/A	NP_001317692.1
	IDH3B	NM_174855.4		c.1072-402C>A		intron	N/A	NP_777280.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDH3B	ENST00000380843.9	TSL:1 MANE Select	c.1072-87C>A		intron	N/A	ENSP00000370223.4
	IDH3B	ENST00000474315.5	TSL:1	c.1072-87C>A		intron	N/A	ENSP00000482773.1
	IDH3B	ENST00000380851.10	TSL:1	c.1072-402C>A		intron	N/A	ENSP00000370232.5

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47783 AN: 151880 Hom.: 7988 Cov.: 32

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.269 AC: 386455 AN: 1435328 Hom.: 53333 Cov.: 30 AF XY: 0.268 AC XY: 190858 AN XY: 712570

African (AFR) AF: 0.420 AC: 13687 AN: 32618

American (AMR) AF: 0.394 AC: 16509 AN: 41872

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5581 AN: 25586

East Asian (EAS) AF: 0.266 AC: 10475 AN: 39318

South Asian (SAS) AF: 0.249 AC: 21174 AN: 85018

European-Finnish (FIN) AF: 0.256 AC: 12160 AN: 47478

Middle Eastern (MID) AF: 0.277 AC: 1199 AN: 4334

European-Non Finnish (NFE) AF: 0.263 AC: 288850 AN: 1099758

Other (OTH) AF: 0.283 AC: 16820 AN: 59346

GnomAD4 genome AF: 0.315 AC: 47839 AN: 152000 Hom.: 7999 Cov.: 32 AF XY: 0.313 AC XY: 23251 AN XY: 74300

African (AFR) AF: 0.414 AC: 17151 AN: 41412

American (AMR) AF: 0.369 AC: 5635 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 760 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1386 AN: 5168

South Asian (SAS) AF: 0.255 AC: 1228 AN: 4818

European-Finnish (FIN) AF: 0.232 AC: 2453 AN: 10564

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18284 AN: 67976

Other (OTH) AF: 0.305 AC: 644 AN: 2110

Alfa AF: 0.282 Hom.: 25183

Bravo AF: 0.329

Asia WGS AF: 0.326 AC: 1134 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.67
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs6037255; hg19: chr20-2639570;