6-33640439-G-T

Variant names:

• chr6-33640439-G-T
• rs41271247
• NM_002224.4:c.90-45G>T

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.90-45G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,580,972 control chromosomes in the GnomAD database, including 12,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (840 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11534 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.732
• Publications: 5 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=-0.87).
• BP6: Variant 6-33640439-G-T is Benign according to our data. Variant chr6-33640439-G-T is described in ClinVar as [Benign]. Clinvar id is 1293544.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.90-45G>T		intron_variant	Intron 1 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.90-45G>T		intron_variant	Intron 1 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.90-45G>T		intron_variant	Intron 2 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15508 AN: 152168 Hom.: 838 Cov.: 32

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0839

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0856

GnomAD2 exomes AF: 0.101 AC: 23852 AN: 235190 AF XY: 0.0999

Gnomad AFR exome AF: 0.0878

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0593

Gnomad EAS exome AF: 0.0154

Gnomad FIN exome AF: 0.0852

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.122 AC: 174935 AN: 1428686 Hom.: 11534 Cov.: 26 AF XY: 0.121 AC XY: 86028 AN XY: 711360

African (AFR) AF: 0.0797 AC: 2596 AN: 32570

American (AMR) AF: 0.126 AC: 5263 AN: 41858

Ashkenazi Jewish (ASJ) AF: 0.0630 AC: 1566 AN: 24858

East Asian (EAS) AF: 0.0330 AC: 1287 AN: 38946

South Asian (SAS) AF: 0.0873 AC: 7284 AN: 83402

European-Finnish (FIN) AF: 0.0911 AC: 4785 AN: 52520

Middle Eastern (MID) AF: 0.0844 AC: 474 AN: 5614

European-Non Finnish (NFE) AF: 0.133 AC: 144981 AN: 1089916

Other (OTH) AF: 0.114 AC: 6699 AN: 59002

GnomAD4 genome AF: 0.102 AC: 15518 AN: 152286 Hom.: 840 Cov.: 32 AF XY: 0.0986 AC XY: 7339 AN XY: 74460

African (AFR) AF: 0.0916 AC: 3806 AN: 41548

American (AMR) AF: 0.102 AC: 1559 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3470

East Asian (EAS) AF: 0.0212 AC: 110 AN: 5188

South Asian (SAS) AF: 0.0836 AC: 404 AN: 4834

European-Finnish (FIN) AF: 0.0812 AC: 862 AN: 10620

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8237 AN: 68006

Other (OTH) AF: 0.0848 AC: 179 AN: 2112

Alfa AF: 0.109 Hom.: 774

Bravo AF: 0.103

Asia WGS AF: 0.0690 AC: 241 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	-0.87
CADD	Benign	3.2
DANN	Benign	0.74
PhyloP100		0.73
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: rs41271247; hg19: chr6-33608216;