3-4788144-G-T

Variant names:

• chr3-4788144-G-T
• rs878853174
• NM_001378452.1:c.6808+5G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001378452.1(ITPR1):​c.6808+5G>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.30
• Publications: 2 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-4788144-G-T is Pathogenic according to our data. Variant chr3-4788144-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 235918.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6808+5G>T		splice_region_variant, intron_variant	Intron 52 of 61	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6763+5G>T		splice_region_variant, intron_variant	Intron 51 of 60		NP_001161744.1
ITPR1	NM_001099952.4	c.6664+5G>T		splice_region_variant, intron_variant	Intron 49 of 58		NP_001093422.2
ITPR1	NM_002222.7	c.6619+5G>T		splice_region_variant, intron_variant	Intron 48 of 57		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6808+5G>T		splice_region_variant, intron_variant	Intron 52 of 61		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.6784+5G>T		splice_region_variant, intron_variant	Intron 52 of 61	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.6781+5G>T		splice_region_variant, intron_variant	Intron 52 of 61			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.6766+5G>T		splice_region_variant, intron_variant	Intron 51 of 60			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6763+5G>T		splice_region_variant, intron_variant	Intron 51 of 60	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6736+5G>T		splice_region_variant, intron_variant	Intron 49 of 58			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6664+5G>T		splice_region_variant, intron_variant	Intron 49 of 58	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6619+5G>T		splice_region_variant, intron_variant	Intron 48 of 57	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4570+5G>T		splice_region_variant, intron_variant	Intron 32 of 41			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4108+5G>T		splice_region_variant, intron_variant	Intron 30 of 38			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3715+5G>T		splice_region_variant, intron_variant	Intron 28 of 38			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gillespie syndrome Pathogenic:1

Jul 20, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		7.3
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: -5

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

Other links and lift over

dbSNP: rs878853174; hg19: chr3-4829828;