6-33655890-A-ATG

Variant names:

• chr6-33655890-A-ATG
• rs149835704
• NM_002224.4:c.282+14_282+15dupTG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000605930.3(ITPR3):​c.282+3_282+4insTG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,244 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (14 hom.)
• Consequence: ITPR3 ENST00000605930.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.480
• Publications: 1 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 -12 ACMG points.

• BP6: Variant 6-33655890-A-ATG is Benign according to our data. Variant chr6-33655890-A-ATG is described in ClinVar as [Likely_benign]. Clinvar id is 1170819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 603 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.282+14_282+15dupTG		intron_variant	Intron 3 of 57	ENST00000605930.3	NP_002215.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3	c.282+3_282+4insTG		splice_region_variant, intron_variant	Intron 3 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.282+3_282+4insTG		splice_region_variant, intron_variant	Intron 4 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 152078 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00243 AC: 607 AN: 249674 AF XY: 0.00244

Gnomad AFR exome AF: 0.00968

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00163 AC: 2382 AN: 1461048 Hom.: 14 Cov.: 31 AF XY: 0.00167 AC XY: 1211 AN XY: 726840

African (AFR) AF: 0.00855 AC: 286 AN: 33468

American (AMR) AF: 0.00300 AC: 134 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26112

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39670

South Asian (SAS) AF: 0.00383 AC: 330 AN: 86242

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53266

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5764

European-Non Finnish (NFE) AF: 0.00120 AC: 1330 AN: 1111466

Other (OTH) AF: 0.00283 AC: 171 AN: 60350

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152196 Hom.: 5 Cov.: 32 AF XY: 0.00414 AC XY: 308 AN XY: 74422

African (AFR) AF: 0.00975 AC: 405 AN: 41536

American (AMR) AF: 0.00320 AC: 49 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 67998

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00327 Hom.: 1

Bravo AF: 0.00440

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00257

EpiControl AF: 0.00303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR3: BS2 -

Apr 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149835704; hg19: chr6-33623667;