Genetic Variant NM_002224.4:c.529-81T>C (chr6-33658940-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002224.4(ITPR3):c.529-81T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,598,006 control chromosomes in the GnomAD database, including 70,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.23 ( 4728 hom., cov: 32)

Exomes 𝑓: 0.29 ( 65407 hom. )

Consequence

ITPR3
NM_002224.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.71

Publications

19 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 6-33658940-T-C is Benign according to our data. Variant chr6-33658940-T-C is described in ClinVar as [Benign]. Clinvar id is 1251010.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR3	NM_002224.4 link	c.529-81T>C		intron_variant	Intron 5 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.529-81T>C		intron_variant	Intron 5 of 57	1	NM_002224.4	ENSP00000475177.1		Q14573
ITPR3	ENST00000374316.9 link	c.529-81T>C		intron_variant	Intron 6 of 58	5		ENSP00000363435.4		Q14573

Frequencies

GnomAD3 genomes

AF:

0.231

AC:

35042

AN:

151968

Hom.:

4728

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0990

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.440

Gnomad SAS

AF:

0.397

Gnomad FIN

AF:

0.288

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.216

GnomAD4 exome

AF:

0.295

AC:

425982

AN:

1445920

Hom.:

65407

Cov.:

AF XY:

0.298

AC XY:

213918

AN XY:

718986

show subpopulations

African (AFR)

AF:

0.0917

AC:

3042

AN:

33158

American (AMR)

AF:

0.228

AC:

10155

AN:

44444

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

4412

AN:

25616

East Asian (EAS)

AF:

0.438

AC:

17315

AN:

39504

South Asian (SAS)

AF:

0.392

AC:

33479

AN:

85402

European-Finnish (FIN)

AF:

0.301

AC:

15958

AN:

53076

Middle Eastern (MID)

AF:

0.207

AC:

1181

AN:

5714

European-Non Finnish (NFE)

AF:

0.294

AC:

323640

AN:

1099308

Other (OTH)

AF:

0.281

AC:

16800

AN:

59698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

16100

32199

48299

64398

80498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.231

AC:

35057

AN:

152086

Hom.:

4728

Cov.:

AF XY:

0.235

AC XY:

17430

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0990

AC:

4113

AN:

41530

American (AMR)

AF:

0.222

AC:

3399

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

597

AN:

3470

East Asian (EAS)

AF:

0.440

AC:

2269

AN:

5154

South Asian (SAS)

AF:

0.397

AC:

1911

AN:

4810

European-Finnish (FIN)

AF:

0.288

AC:

3041

AN:

10576

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18907

AN:

67946

Other (OTH)

AF:

0.214

AC:

453

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1351

2703

4054

5406

6757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.271

Hom.:

22681

Bravo

AF:

0.218

Asia WGS

AF:

0.399

AC:

1386

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

-0.61

CADD

Benign

0.47

(source)

DANN

Benign

0.86

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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NM_002224.4:c.529-81T>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