chr6-33657923-T-A

Variant names:

• chr6-33657923-T-A
• NM_002224.4:c.283-9T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002224.4(ITPR3):​c.283-9T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR3 NM_002224.4 intron
• Scores: Splicing: ADA: 0.9552
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.274
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002224.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	NM_002224.4	MANE Select	c.283-9T>A		intron	N/A	NP_002215.2	Q14573

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.283-9T>A		intron	N/A	ENSP00000475177.1	Q14573
	ITPR3	ENST00000374316.9	TSL:5	c.283-9T>A		intron	N/A	ENSP00000363435.4	Q14573
	ITPR3	ENST00000931640.1		c.283-9T>A		intron	N/A	ENSP00000601699.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	ITPR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	28
DANN	Benign	0.84
PhyloP100		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.62
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.63		Position offset: -37

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

Other links and lift over

hg19: chr6-33625700;