Genetic Variant ITPR3:c.-395C>A (chr6-33621208-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

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

The ENST00000374316.9(ITPR3):c.-395C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 141,474 control chromosomes in the GnomAD database, including 1,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.14 ( 1732 hom., cov: 30)

Exomes 𝑓: 0.18 ( 10 hom. )

Consequence

ITPR3
ENST00000374316.9 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.09

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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=-0.69).

BP6

Variant 6-33621208-C-A is Benign according to our data. Variant chr6-33621208-C-A is described in ClinVar as Benign. ClinVar VariationId is 1284184.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374316.9. 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.-395C>A		upstream_gene	N/A	NP_002215.2	Q14573

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ITPR3	ENST00000374316.9	TSL:5	c.-395C>A	5_prime_UTR	Exon 2 of 59	ENSP00000363435.4	Q14573
ITPR3	ENST00000605930.3	TSL:1 MANE Select	c.-395C>A	upstream_gene	N/A	ENSP00000475177.1	Q14573
ITPR3	ENST00000931640.1		c.-395C>A	upstream_gene	N/A	ENSP00000601699.1

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

19343

AN:

140946

Hom.:

1731

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0355

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.00969

Gnomad SAS

AF:

0.0752

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.205

Gnomad NFE

AF:

0.197

Gnomad OTH

AF:

0.157

GnomAD4 exome

AF:

0.176

AC:

AN:

432

Hom.:

Cov.:

AF XY:

0.208

AC XY:

AN XY:

274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.167

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.100

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AF:

0.333

AC:

AN:

European-Non Finnish (NFE)

AF:

0.190

AC:

AN:

336

Other (OTH)

AF:

0.200

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.137

AC:

19342

AN:

141042

Hom.:

1732

Cov.:

AF XY:

0.132

AC XY:

9085

AN XY:

68626

show subpopulations

African (AFR)

AF:

0.0354

AC:

1362

AN:

38456

American (AMR)

AF:

0.150

AC:

2173

AN:

14452

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

777

AN:

3364

East Asian (EAS)

AF:

0.00971

AC:

AN:

4016

South Asian (SAS)

AF:

0.0749

AC:

293

AN:

3914

European-Finnish (FIN)

AF:

0.161

AC:

1425

AN:

8852

Middle Eastern (MID)

AF:

0.220

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.197

AC:

12764

AN:

64848

Other (OTH)

AF:

0.155

AC:

312

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

795

1590

2384

3179

3974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0769

Hom.:

124

Bravo

AF:

0.127

Asia WGS

AF:

0.0410

AC:

142

AN:

3456

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.1

PromoterAI

0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over