rs397514536

Variant names:

• chr3-4667467-A-C
• rs397514536
• NM_001378452.1:c.1804A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-4667467-A-C
• chr3-4667467-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001378452.1(ITPR1):​c.1804A>C​(p.Asn602His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N602D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr3-4667467-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 39572.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.1804A>C	p.Asn602His	missense_variant	Exon 18 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1759A>C	p.Asn587His	missense_variant	Exon 17 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.1804A>C	p.Asn602His	missense_variant	Exon 18 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.1759A>C	p.Asn587His	missense_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.1804A>C	p.Asn602His	missense_variant	Exon 18 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1804A>C	p.Asn602His	missense_variant	Exon 18 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1804A>C	p.Asn602His	missense_variant	Exon 18 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1759A>C	p.Asn587His	missense_variant	Exon 17 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1759A>C	p.Asn587His	missense_variant	Exon 17 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1759A>C	p.Asn587His	missense_variant	Exon 15 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1804A>C	p.Asn602His	missense_variant	Exon 18 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1759A>C	p.Asn587His	missense_variant	Exon 17 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;M;.;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;.;.;.;.;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;.;D;.;.;.;.;D
Polyphen		0.94	.;.;.;.;.;.;P;.;.
Vest4		0.86
MutPred		0.78		Loss of stability (P = 0.077);.;Loss of stability (P = 0.077);.;Loss of stability (P = 0.077);.;Loss of stability (P = 0.077);.;.;
MVP		0.97
MPC		1.5
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.60
gMVP		0.98
Mutation Taster		=27/73	disease causing

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: rs397514536; hg19: chr3-4709151;