Genetic Variant NM_002224.4:c.283-13T>C (chr6-33657919-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_002224.4(ITPR3):c.283-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,611,136 control chromosomes in the GnomAD database, including 45,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.20 ( 3762 hom., cov: 31)

Exomes 𝑓: 0.23 ( 42135 hom. )

Consequence

ITPR3
NM_002224.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.194

Publications

14 publications found

Variant links:

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

ITPR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 6-33657919-T-C is Benign according to our data. Variant chr6-33657919-T-C is described in ClinVar as [Benign]. Clinvar id is 1251103.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4 link	c.283-13T>C		intron_variant	Intron 3 of 57	ENST00000605930.3	NP_002215.2	Q14573A6H8K3Q59ES2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR3	ENST00000605930.3 link	c.283-13T>C		intron_variant	Intron 3 of 57	1	NM_002224.4	ENSP00000475177.1		Q14573
ITPR3	ENST00000374316.9 link	c.283-13T>C		intron_variant	Intron 4 of 58	5		ENSP00000363435.4		Q14573

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

30764

AN:

151790

Hom.:

3765

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0641

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.294

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.174

GnomAD2 exomes

AF:

0.257

AC:

64141

AN:

249106

AF XY:

0.260

show subpopulations

Gnomad AFR exome

AF:

0.0580

Gnomad AMR exome

AF:

0.329

Gnomad ASJ exome

AF:

0.267

Gnomad EAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.343

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.235

AC:

342860

AN:

1459228

Hom.:

42135

Cov.:

AF XY:

0.238

AC XY:

172447

AN XY:

725908

show subpopulations

African (AFR)

AF:

0.0552

AC:

1847

AN:

33448

American (AMR)

AF:

0.319

AC:

14208

AN:

44472

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6980

AN:

26100

East Asian (EAS)

AF:

0.263

AC:

10430

AN:

39622

South Asian (SAS)

AF:

0.284

AC:

24435

AN:

86078

European-Finnish (FIN)

AF:

0.336

AC:

17855

AN:

53176

Middle Eastern (MID)

AF:

0.207

AC:

1191

AN:

5760

European-Non Finnish (NFE)

AF:

0.227

AC:

252412

AN:

1110290

Other (OTH)

AF:

0.224

AC:

13502

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

13892

27784

41677

55569

69461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.203

AC:

30762

AN:

151908

Hom.:

3762

Cov.:

AF XY:

0.211

AC XY:

15639

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.0639

AC:

2650

AN:

41452

American (AMR)

AF:

0.254

AC:

3880

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.284

AC:

983

AN:

3462

East Asian (EAS)

AF:

0.281

AC:

1449

AN:

5164

South Asian (SAS)

AF:

0.295

AC:

1418

AN:

4808

European-Finnish (FIN)

AF:

0.351

AC:

3694

AN:

10536

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.236

AC:

16043

AN:

67910

Other (OTH)

AF:

0.173

AC:

366

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1233

2466

3698

4931

6164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.211

Hom.:

5413

Bravo

AF:

0.188

Asia WGS

AF:

0.220

AC:

767

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 04, 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

-0.68

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.36

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.36

Position offset: -33

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

Publications

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NM_002224.4:c.283-13T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over