6-33621555-C-T

Variant names:

• chr6-33621555-C-T
• rs55774724
• NM_002224.4:c.-48C>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.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0588 in 1,445,402 control chromosomes in the GnomAD database, including 2,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.050 (231 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2592 hom.)
• Consequence: ITPR3 NM_002224.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.348
• Publications: 4 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=-0.48).
• BP6: Variant 6-33621555-C-T is Benign according to our data. Variant chr6-33621555-C-T is described in ClinVar as [Benign]. Clinvar id is 1246493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 58	ENST00000605930.3	NP_002215.2
ITPR3	NM_002224.4	c.-48C>T		5_prime_UTR_variant	Exon 1 of 58	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 58	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000605930.3	c.-48C>T		5_prime_UTR_variant	Exon 1 of 58	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.-48C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 59	5		ENSP00000363435.4
ITPR3	ENST00000374316.9	c.-48C>T		5_prime_UTR_variant	Exon 2 of 59	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7584 AN: 152162 Hom.: 231 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0619

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.0429

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0580

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0539 AC: 8730 AN: 161968 AF XY: 0.0527

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.0507

Gnomad ASJ exome AF: 0.0634

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.0457

Gnomad NFE exome AF: 0.0593

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0599 AC: 77409 AN: 1293124 Hom.: 2592 Cov.: 19 AF XY: 0.0581 AC XY: 37415 AN XY: 644050

African (AFR) AF: 0.0279 AC: 826 AN: 29594

American (AMR) AF: 0.0498 AC: 1786 AN: 35832

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1542 AN: 24556

East Asian (EAS) AF: 0.0987 AC: 3540 AN: 35850

South Asian (SAS) AF: 0.0140 AC: 1085 AN: 77702

European-Finnish (FIN) AF: 0.0498 AC: 2441 AN: 49020

Middle Eastern (MID) AF: 0.0390 AC: 214 AN: 5490

European-Non Finnish (NFE) AF: 0.0637 AC: 62457 AN: 980612

Other (OTH) AF: 0.0646 AC: 3518 AN: 54468

GnomAD4 genome AF: 0.0498 AC: 7586 AN: 152278 Hom.: 231 Cov.: 32 AF XY: 0.0496 AC XY: 3696 AN XY: 74466

African (AFR) AF: 0.0322 AC: 1338 AN: 41580

American (AMR) AF: 0.0490 AC: 751 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 215 AN: 3472

East Asian (EAS) AF: 0.124 AC: 641 AN: 5156

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4832

European-Finnish (FIN) AF: 0.0429 AC: 455 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0580 AC: 3944 AN: 68000

Other (OTH) AF: 0.0444 AC: 94 AN: 2116

Alfa AF: 0.0515 Hom.: 45

Bravo AF: 0.0522

Asia WGS AF: 0.0640 AC: 221 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	-0.48
CADD	Benign	12
DANN	Benign	0.97
PhyloP100		-0.35
PromoterAI		0.016	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs55774724; hg19: chr6-33589332;