NM_002224.4:c.2729-46G>C

Variant names:

• chr6-33671983-G-C
• rs3736893
• NM_002224.4:c.2729-46G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002224.4(ITPR3):​c.2729-46G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,541,314 control chromosomes in the GnomAD database, including 361,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (36973 hom., cov: 30)
  • Exomes 𝑓: 0.68 (324245 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.916
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-33671983-G-C is Benign according to our data. Variant chr6-33671983-G-C is described in ClinVar as Benign. ClinVar VariationId is 1182536.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.853 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	NM_002224.4	MANE Select	c.2729-46G>C		intron	N/A	NP_002215.2	Q14573

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.2729-46G>C		intron	N/A	ENSP00000475177.1	Q14573
	ITPR3	ENST00000374316.9	TSL:5	c.2729-46G>C		intron	N/A	ENSP00000363435.4	Q14573
	ITPR3	ENST00000931640.1		c.2729-46G>C		intron	N/A	ENSP00000601699.1

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105329 AN: 151732 Hom.: 36926 Cov.: 30

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.774

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.713 AC: 147801 AN: 207290 AF XY: 0.716

Gnomad AFR exome AF: 0.733

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.615

Gnomad EAS exome AF: 0.839

Gnomad FIN exome AF: 0.769

Gnomad NFE exome AF: 0.648

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.680 AC: 944664 AN: 1389464 Hom.: 324245 Cov.: 24 AF XY: 0.684 AC XY: 468973 AN XY: 685234

African (AFR) AF: 0.732 AC: 23280 AN: 31810

American (AMR) AF: 0.714 AC: 27811 AN: 38944

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 13577 AN: 21934

East Asian (EAS) AF: 0.847 AC: 33198 AN: 39172

South Asian (SAS) AF: 0.855 AC: 64765 AN: 75728

European-Finnish (FIN) AF: 0.761 AC: 38627 AN: 50748

Middle Eastern (MID) AF: 0.633 AC: 2576 AN: 4068

European-Non Finnish (NFE) AF: 0.656 AC: 701892 AN: 1069712

Other (OTH) AF: 0.679 AC: 38938 AN: 57348

GnomAD4 genome AF: 0.694 AC: 105435 AN: 151850 Hom.: 36973 Cov.: 30 AF XY: 0.704 AC XY: 52225 AN XY: 74232

African (AFR) AF: 0.726 AC: 30022 AN: 41362

American (AMR) AF: 0.671 AC: 10248 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2197 AN: 3472

East Asian (EAS) AF: 0.835 AC: 4292 AN: 5138

South Asian (SAS) AF: 0.875 AC: 4209 AN: 4808

European-Finnish (FIN) AF: 0.774 AC: 8179 AN: 10566

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44119 AN: 67918

Other (OTH) AF: 0.662 AC: 1396 AN: 2108

Alfa AF: 0.656 Hom.: 6211

Bravo AF: 0.684

Asia WGS AF: 0.857 AC: 2978 AN: 3478

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.94
DANN	Benign	0.33
PhyloP100		-0.92
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3736893;

hg19: chr6-33639760;

COSMIC: COSV65406801;