6-33689469-C-T

Variant names:

• chr6-33689469-C-T
• rs3818521
• NM_002224.4:c.6867+59C>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.6867+59C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 1,573,584 control chromosomes in the GnomAD database, including 180,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (15253 hom., cov: 33)
  • Exomes 𝑓: 0.47 (165183 hom.)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.238
• Publications: 10 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=-0.81).
• BP6: Variant 6-33689469-C-T is Benign according to our data. Variant chr6-33689469-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.6867+59C>T		intron_variant	Intron 50 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.6867+59C>T		intron_variant	Intron 50 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.6867+59C>T		intron_variant	Intron 51 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62305 AN: 152014 Hom.: 15250 Cov.: 33

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.469 AC: 667169 AN: 1421452 Hom.: 165183 AF XY: 0.478 AC XY: 337150 AN XY: 705778

African (AFR) AF: 0.157 AC: 5181 AN: 32924

American (AMR) AF: 0.614 AC: 26755 AN: 43598

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11602 AN: 25174

East Asian (EAS) AF: 0.819 AC: 32161 AN: 39290

South Asian (SAS) AF: 0.701 AC: 59072 AN: 84218

European-Finnish (FIN) AF: 0.587 AC: 23388 AN: 39844

Middle Eastern (MID) AF: 0.427 AC: 2427 AN: 5686

European-Non Finnish (NFE) AF: 0.439 AC: 479104 AN: 1091418

Other (OTH) AF: 0.463 AC: 27479 AN: 59300

GnomAD4 genome AF: 0.410 AC: 62316 AN: 152132 Hom.: 15253 Cov.: 33 AF XY: 0.429 AC XY: 31885 AN XY: 74380

African (AFR) AF: 0.166 AC: 6889 AN: 41518

American (AMR) AF: 0.511 AC: 7815 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1628 AN: 3472

East Asian (EAS) AF: 0.853 AC: 4407 AN: 5168

South Asian (SAS) AF: 0.720 AC: 3473 AN: 4826

European-Finnish (FIN) AF: 0.606 AC: 6416 AN: 10592

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30286 AN: 67952

Other (OTH) AF: 0.386 AC: 815 AN: 2110

Alfa AF: 0.306 Hom.: 3216

Bravo AF: 0.388

Asia WGS AF: 0.695 AC: 2417 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.55
PhyloP100		0.24
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: rs3818521; hg19: chr6-33657246; COSMIC: COSV65409484; COSMIC: COSV65409484;