3-4693723-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.4263C>G​(p.His1421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,612,892 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1421H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.56
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009713441).
• BP6: Variant 3-4693723-C-G is Benign according to our data. Variant chr3-4693723-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00503 (766/152348) while in subpopulation AFR AF = 0.014 (582/41592). AF 95% confidence interval is 0.0131. There are 7 homozygotes in GnomAd4. There are 351 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.4263C>G	p.His1421Gln	missense	Exon 33 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.4218C>G	p.His1406Gln	missense	Exon 32 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.4236C>G	p.His1412Gln	missense	Exon 33 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.4263C>G	p.His1421Gln	missense	Exon 33 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.4236C>G	p.His1412Gln	missense	Exon 33 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.4236C>G	p.His1412Gln	missense	Exon 33 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 768 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00215 AC: 531 AN: 246696 AF XY: 0.00180

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00126 AC: 1845 AN: 1460544 Hom.: 5 Cov.: 31 AF XY: 0.00122 AC XY: 888 AN XY: 726432

African (AFR) AF: 0.0162 AC: 542 AN: 33446

American (AMR) AF: 0.00515 AC: 229 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86118

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000691 AC: 768 AN: 1111296

Other (OTH) AF: 0.00297 AC: 179 AN: 60354

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74498

African (AFR) AF: 0.0140 AC: 582 AN: 41592

American (AMR) AF: 0.00673 AC: 103 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68030

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00606

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Dec 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 20, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR1: PP3, BS1

not specified Benign:1

May 22, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant cerebellar ataxia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.25	T
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	0.30	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0097	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		-1.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.37		Loss of catalytic residue at D1423 (P = 0.1755)
MVP		0.85
MPC		1.5
ClinPred		0.12	T
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;