6-33656956-A-G

Variant names:

• chr6-33656956-A-G
• rs999943
• NM_002224.4:c.283-976A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002224.4(ITPR3):​c.283-976A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 152,100 control chromosomes in the GnomAD database, including 6,278 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6278 hom., cov: 33)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0760
• Publications: 23 publications found

Genes affected

ITPR3 (HGNC:6182): (inositol 1,4,5-trisphosphate receptor type 3) This gene encodes a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. The receptor contains a calcium channel at the C-terminus and the ligand-binding site at the N-terminus. Knockout studies in mice suggest that type 2 and type 3 inositol 1,4,5-trisphosphate receptors play a key role in exocrine secretion underlying energy metabolism and growth. [provided by RefSeq, Aug 2010]

ITPR3 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease, demyelinating, type 1J

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002224.4. 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
	ITPR3	NM_002224.4	MANE Select	c.283-976A>G		intron	N/A	NP_002215.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.283-976A>G		intron	N/A	ENSP00000475177.1
	ITPR3	ENST00000374316.9	TSL:5	c.283-976A>G		intron	N/A	ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43037 AN: 151982 Hom.: 6277 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.283 AC: 43067 AN: 152100 Hom.: 6278 Cov.: 33 AF XY: 0.288 AC XY: 21442 AN XY: 74340

African (AFR) AF: 0.237 AC: 9846 AN: 41488

American (AMR) AF: 0.312 AC: 4783 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1148 AN: 3472

East Asian (EAS) AF: 0.291 AC: 1495 AN: 5140

South Asian (SAS) AF: 0.309 AC: 1485 AN: 4806

European-Finnish (FIN) AF: 0.372 AC: 3933 AN: 10586

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19518 AN: 67978

Other (OTH) AF: 0.251 AC: 530 AN: 2114

Alfa AF: 0.287 Hom.: 22488

Bravo AF: 0.276

Asia WGS AF: 0.239 AC: 834 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.69
PhyloP100		-0.076
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: rs999943; hg19: chr6-33624733;