NM_002224.4:c.1148+39G>A

Variant names:

• chr6-33663919-G-A
• rs2296337
• NM_002224.4:c.1148+39G>A

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.1148+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,609,442 control chromosomes in the GnomAD database, including 69,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4866 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64994 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.61
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-33663919-G-A is Benign according to our data. Variant chr6-33663919-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269800.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.1148+39G>A		intron_variant	Intron 11 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.1148+39G>A		intron_variant	Intron 11 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.1148+39G>A		intron_variant	Intron 12 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36574 AN: 151944 Hom.: 4863 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.286 AC: 70648 AN: 247188 AF XY: 0.294

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.435

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.294 AC: 427826 AN: 1457380 Hom.: 64994 Cov.: 34 AF XY: 0.296 AC XY: 214483 AN XY: 724776

African (AFR) AF: 0.132 AC: 4426 AN: 33446

American (AMR) AF: 0.241 AC: 10737 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4474 AN: 25886

East Asian (EAS) AF: 0.437 AC: 17327 AN: 39656

South Asian (SAS) AF: 0.378 AC: 32506 AN: 85954

European-Finnish (FIN) AF: 0.302 AC: 15895 AN: 52578

Middle Eastern (MID) AF: 0.207 AC: 1167 AN: 5630

European-Non Finnish (NFE) AF: 0.292 AC: 324303 AN: 1109496

Other (OTH) AF: 0.282 AC: 16991 AN: 60212

GnomAD4 genome AF: 0.241 AC: 36598 AN: 152062 Hom.: 4866 Cov.: 32 AF XY: 0.245 AC XY: 18186 AN XY: 74310

African (AFR) AF: 0.136 AC: 5649 AN: 41516

American (AMR) AF: 0.234 AC: 3573 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 594 AN: 3472

East Asian (EAS) AF: 0.435 AC: 2244 AN: 5160

South Asian (SAS) AF: 0.380 AC: 1827 AN: 4806

European-Finnish (FIN) AF: 0.292 AC: 3084 AN: 10572

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18785 AN: 67932

Other (OTH) AF: 0.225 AC: 476 AN: 2114

Alfa AF: 0.262 Hom.: 7748

Bravo AF: 0.231

Asia WGS AF: 0.396 AC: 1376 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.82
CADD	Benign	1.7
DANN	Benign	0.84
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2296337; hg19: chr6-33631696; COSMIC: COSV65406870;