rs3749383

Positions:

• chr3-4697153-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.4288A>G​(p.Ile1430Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,610,434 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (44 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.42

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0076238215).
• BP6: Variant 3-4697153-A-G is Benign according to our data. Variant chr3-4697153-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 345737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00137 (209/152300) while in subpopulation EAS AF= 0.0359 (186/5176). AF 95% confidence interval is 0.0317. There are 6 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4288A>G	p.Ile1430Val	missense_variant	34/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4243A>G	p.Ile1415Val	missense_variant	33/61		NP_001161744.1
ITPR1	NM_001099952.4	c.4261A>G	p.Ile1421Val	missense_variant	34/59		NP_001093422.2
ITPR1	NM_002222.7	c.4216A>G	p.Ile1406Val	missense_variant	33/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4288A>G	p.Ile1430Val	missense_variant	34/62		NM_001378452.1	ENSP00000497605

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152182 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0359

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00287 AC: 699 AN: 243204 Hom.: 14 AF XY: 0.00276 AC XY: 364 AN XY: 131736

Gnomad AFR exome AF: 0.000336

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0377

Gnomad SAS exome AF: 0.000474

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00119 AC: 1741 AN: 1458134 Hom.: 44 Cov.: 32 AF XY: 0.00116 AC XY: 844 AN XY: 724910

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0368

Gnomad4 SAS exome AF: 0.000820

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152300 Hom.: 6 Cov.: 31 AF XY: 0.00160 AC XY: 119 AN XY: 74474

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0359

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00136 Hom.: 6

Bravo AF: 0.00161

ESP6500AA AF: 0.000531 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00291 AC: 351

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 15, 2020

- -

Gillespie syndrome;C1847725:Spinocerebellar ataxia type 15/16;C1861732:Spinocerebellar ataxia type 29 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	0.0011
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	.;.;.;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.15	N;N;.;N;.;.;.;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.30	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.28	T;T;.;T;.;.;.;.;T;.
Polyphen		0.059	.;.;.;.;.;.;B;.;.;.
Vest4		0.28
MVP		0.21
MPC		0.64
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.097
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs3749383; hg19: chr3-4738837;