rs752379221

Variant names:

• chr3-4667382-T-C
• rs752379221
• NM_001378452.1:c.1719T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001378452.1(ITPR1):​c.1719T>C​(p.Tyr573Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,453,812 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (1 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.159
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-4667382-T-C is Benign according to our data. Variant chr3-4667382-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 586040.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.159 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.1719T>C	p.Tyr573Tyr	synonymous_variant	Exon 18 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1674T>C	p.Tyr558Tyr	synonymous_variant	Exon 17 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.1719T>C	p.Tyr573Tyr	synonymous_variant	Exon 18 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.1674T>C	p.Tyr558Tyr	synonymous_variant	Exon 17 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.1719T>C	p.Tyr573Tyr	synonymous_variant	Exon 18 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1719T>C	p.Tyr573Tyr	synonymous_variant	Exon 18 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1719T>C	p.Tyr573Tyr	synonymous_variant	Exon 18 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1674T>C	p.Tyr558Tyr	synonymous_variant	Exon 17 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1674T>C	p.Tyr558Tyr	synonymous_variant	Exon 17 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1674T>C	p.Tyr558Tyr	synonymous_variant	Exon 15 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1719T>C	p.Tyr573Tyr	synonymous_variant	Exon 18 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1674T>C	p.Tyr558Tyr	synonymous_variant	Exon 17 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000127 AC: 3 AN: 236662 AF XY: 0.00000781

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1453812 Hom.: 1 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 722228

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 43540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000827 AC: 7 AN: 84608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107814

Other (OTH) AF: 0.00 AC: 0 AN: 60110

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 14, 2018

Athena Diagnostics

Significance: Likely 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	-0.58
CADD	Benign	5.3
DANN	Benign	0.47
PhyloP100		0.16

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: rs752379221; hg19: chr3-4709066;