rs397514535

Variant names:

• chr3-4706193-G-A
• rs397514535
• NM_001378452.1:c.4684G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM2 PP5

The NM_001378452.1(ITPR1):​c.4684G>A​(p.Val1562Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005874581: Published functional studies demonstrate a damaging effect: abolished interaction with carbonic anhydrase-related protein VIII (CA8) and CA8-mediated inhibition of ITPR1 (PMID:30429331)".

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:1
• Conservation: PhyloP100: 6.69
• Publications: 15 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

LOC124906210 (HGNC:):

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005874581: Published functional studies demonstrate a damaging effect: abolished interaction with carbonic anhydrase-related protein VIII (CA8) and CA8-mediated inhibition of ITPR1 (PMID: 30429331)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-4706193-G-A is Pathogenic according to our data. Variant chr3-4706193-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39571.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. 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
	ITPR1	NM_001378452.1	MANE Select	c.4684G>A	p.Val1562Met	missense	Exon 37 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.4639G>A	p.Val1547Met	missense	Exon 36 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.4657G>A	p.Val1553Met	missense	Exon 37 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.4684G>A	p.Val1562Met	missense	Exon 37 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.4657G>A	p.Val1553Met	missense	Exon 37 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.4657G>A	p.Val1553Met	missense	Exon 37 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000653 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Spinocerebellar ataxia type 29 (3)
-	1	-	Gillespie syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Spinocerebellar ataxia type 15/16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Benign	0.31	T
Sift4G	Benign	0.39	T
Polyphen		1.0	D
Vest4		0.54
MutPred		0.33		Gain of helix (P = 0.062)
MVP		0.65
MPC		1.8
ClinPred		0.96	D
GERP RS		5.4
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.50
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397514535; hg19: chr3-4747877;