rs797044955

Variant names:

• chr3-4645673-C-G
• rs797044955
• NM_001378452.1:c.800C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-4645673-C-G
• chr3-4645673-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.800C>G​(p.Thr267Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T267M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.82
• Publications: 18 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001378452.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4645673-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 3-4645673-C-G is Pathogenic according to our data. Variant chr3-4645673-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 586057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.800C>G	p.Thr267Arg	missense_variant	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.800C>G	p.Thr267Arg	missense_variant	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 15, 2018

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spinocerebellar ataxia type 29 Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.7	M;M;.;.;M;.;.;.;M;M;M
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;D;.;D;D;.;D;.;.;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D;D;.;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;.;.;D;.;D;.;.;.;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;D;.;D;.;.
Vest4		0.98
MutPred		0.75		Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);Gain of methylation at T267 (P = 0.0238);
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.91
gMVP		0.91
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs797044955; hg19: chr3-4687357;