chr3-4683555-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378452.1(ITPR1):c.3327+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,613,760 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 37 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 252 hom. )

Consequence

ITPR1
NM_001378452.1 splice_region, intron

Scores

Splicing: ADA: 0.0002047

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.204

Publications

5 publications found

Variant links:

Genes affected

ITPR1 (HGNC:6180): (inositol 1,4,5-trisphosphate receptor type 1) This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

ITPR1 Gene-Disease associations (from GenCC):

aniridia-cerebellar ataxia-intellectual disability syndrome
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
spinocerebellar ataxia type 29
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
spinocerebellar ataxia type 15/16
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ITPR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 3-4683555-G-A is Benign according to our data. Variant chr3-4683555-G-A is described in ClinVar as Benign. ClinVar VariationId is 345724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1 link	c.3327+4G>A	splice_region_variant, intron_variant	Intron 27 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2 link	c.3282+4G>A	splice_region_variant, intron_variant	Intron 26 of 60		NP_001161744.1	Q14643-2
ITPR1	NM_001099952.4 link	c.3300+4G>A	splice_region_variant, intron_variant	Intron 27 of 58		NP_001093422.2	Q14643-3B4DER3Q59H91
ITPR1	NM_002222.7 link	c.3255+4G>A	splice_region_variant, intron_variant	Intron 26 of 57		NP_002213.5	Q14643-4B4DER3B4DGH1Q59H91

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPR1	ENST00000649015.2 link	c.3327+4G>A	splice_region_variant, intron_variant	Intron 27 of 61		NM_001378452.1	ENSP00000497605.1	Q14643-1
ITPR1	ENST00000354582.12 link	c.3300+4G>A	splice_region_variant, intron_variant	Intron 27 of 61	5		ENSP00000346595.8	A0A3F2YNW8
ITPR1	ENST00000648266.1 link	c.3300+4G>A	splice_region_variant, intron_variant	Intron 27 of 61			ENSP00000498014.1	A0A3B3IU04
ITPR1	ENST00000650294.1 link	c.3282+4G>A	splice_region_variant, intron_variant	Intron 26 of 60			ENSP00000498056.1	A0A3B3ITU8
ITPR1	ENST00000443694.5 link	c.3282+4G>A	splice_region_variant, intron_variant	Intron 26 of 60	1		ENSP00000401671.2	Q14643-2
ITPR1	ENST00000648309.1 link	c.3255+4G>A	splice_region_variant, intron_variant	Intron 24 of 58			ENSP00000497026.1	Q14643-5
ITPR1	ENST00000357086.10 link	c.3300+4G>A	splice_region_variant, intron_variant	Intron 27 of 58	1		ENSP00000349597.4	Q14643-3
ITPR1	ENST00000456211.8 link	c.3255+4G>A	splice_region_variant, intron_variant	Intron 26 of 57	1		ENSP00000397885.2	Q14643-4
ITPR1	ENST00000648038.1 link	c.1137+4G>A	splice_region_variant, intron_variant	Intron 8 of 41			ENSP00000497872.1	A0A3B3ITQ1
ITPR1	ENST00000648431.1 link	c.627+4G>A	splice_region_variant, intron_variant	Intron 5 of 38			ENSP00000498149.1	A0A3B3IU05
ITPR1	ENST00000648212.1 link	c.234+4G>A	splice_region_variant, intron_variant	Intron 3 of 38			ENSP00000498022.1	A0A3B3IU13

Frequencies

GnomAD3 genomes

AF:

0.00838

AC:

1276

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.0675

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0681

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00179

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.0124

AC:

3083

AN:

248984

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00815

Gnomad EAS exome

AF:

0.0697

Gnomad FIN exome

AF:

0.0637

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.00556

AC:

8131

AN:

1461406

Hom.:

252

Cov.:

AF XY:

0.00542

AC XY:

3937

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33474

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00800

AC:

209

AN:

26132

East Asian (EAS)

AF:

0.0854

AC:

3391

AN:

39690

South Asian (SAS)

AF:

0.00172

AC:

148

AN:

86250

European-Finnish (FIN)

AF:

0.0604

AC:

3223

AN:

53396

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000682

AC:

758

AN:

1111606

Other (OTH)

AF:

0.00611

AC:

369

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

498

997

1495

1994

2492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00836

AC:

1274

AN:

152354

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

863

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41584

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.0675

AC:

350

AN:

5188

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0681

AC:

723

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00179

AC:

122

AN:

68040

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00231

Hom.:

Bravo

AF:

0.00390

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 06, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Sep 02, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant cerebellar ataxia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.27

PhyloP100

-0.20

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.030

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over