rs9469541

Variant names:

• chr6-33656045-G-A
• rs9469541
• NM_002224.4:c.282+158G>A

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.282+158G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 152,260 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.026 (168 hom., cov: 32)
• Consequence: ITPR3 NM_002224.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.270
• 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: 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=-0.9).
• BP6: Variant 6-33656045-G-A is Benign according to our data. Variant chr6-33656045-G-A is described in ClinVar as [Benign]. Clinvar id is 1277727.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4	c.282+158G>A		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+158G>A		intron_variant	Intron 3 of 57	1	NM_002224.4	ENSP00000475177.1
ITPR3	ENST00000374316.9	c.282+158G>A		intron_variant	Intron 4 of 58	5		ENSP00000363435.4

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3964 AN: 152142 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.0869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0244

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0261 AC: 3969 AN: 152260 Hom.: 168 Cov.: 32 AF XY: 0.0253 AC XY: 1882 AN XY: 74438

African (AFR) AF: 0.0867 AC: 3602 AN: 41536

American (AMR) AF: 0.0177 AC: 270 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68026

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0216 Hom.: 17

Bravo AF: 0.0298

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 23, 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	-0.90
CADD	Benign	5.9
DANN	Benign	0.74
PhyloP100		0.27
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: rs9469541; hg19: chr6-33623822;