chr3-4693723-C-A

Variant names:

• chr3-4693723-C-A
• rs61757110
• NM_001378452.1:c.4263C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378452.1(ITPR1):​c.4263C>A​(p.His1421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1421H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37755185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4263C>A	p.His1421Gln	missense_variant	Exon 33 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4218C>A	p.His1406Gln	missense_variant	Exon 32 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.4236C>A	p.His1412Gln	missense_variant	Exon 33 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.4191C>A	p.His1397Gln	missense_variant	Exon 32 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4263C>A	p.His1421Gln	missense_variant	Exon 33 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4236C>A	p.His1412Gln	missense_variant	Exon 33 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4236C>A	p.His1412Gln	missense_variant	Exon 33 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4218C>A	p.His1406Gln	missense_variant	Exon 32 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4218C>A	p.His1406Gln	missense_variant	Exon 32 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4191C>A	p.His1397Gln	missense_variant	Exon 30 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4236C>A	p.His1412Gln	missense_variant	Exon 33 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4191C>A	p.His1397Gln	missense_variant	Exon 32 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2073C>A	p.His691Gln	missense_variant	Exon 14 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1563C>A	p.His521Gln	missense_variant	Exon 11 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1170C>A	p.His390Gln	missense_variant	Exon 9 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.90	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;M;.;.;.
PhyloP100		-1.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;.;D;.;.;.;.;D;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.79
MutPred		0.37		.;.;.;.;.;.;Loss of catalytic residue at D1423 (P = 0.1755);.;.;.;
MVP		0.84
MPC		1.5
ClinPred		0.99	D
GERP RS		-9.2
Varity_R		0.68
gMVP		0.74
Mutation Taster		=98/2	polymorphism

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: rs61757110; hg19: chr3-4735407;