rs773030719

Variant names:

• chr3-4691145-T-A
• rs773030719
• NM_001378452.1:c.3830T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PP2 PP3_Moderate BS1_Supporting

The NM_001378452.1(ITPR1):​c.3830T>A​(p.Ile1277Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,605,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense, splice_region
• Scores: Splicing: ADA: 0.3758
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 7.95

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 Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000282 (41/1452788) while in subpopulation MID AF= 0.00226 (13/5744). AF 95% confidence interval is 0.00134. There are 0 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.3830T>A	p.Ile1277Asn	missense_variant, splice_region_variant	Exon 32 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3785T>A	p.Ile1262Asn	missense_variant, splice_region_variant	Exon 31 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3803T>A	p.Ile1268Asn	missense_variant, splice_region_variant	Exon 32 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3758T>A	p.Ile1253Asn	missense_variant, splice_region_variant	Exon 31 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3830T>A	p.Ile1277Asn	missense_variant, splice_region_variant	Exon 32 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3803T>A	p.Ile1268Asn	missense_variant, splice_region_variant	Exon 32 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3803T>A	p.Ile1268Asn	missense_variant, splice_region_variant	Exon 32 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3785T>A	p.Ile1262Asn	missense_variant, splice_region_variant	Exon 31 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3785T>A	p.Ile1262Asn	missense_variant, splice_region_variant	Exon 31 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3758T>A	p.Ile1253Asn	missense_variant, splice_region_variant	Exon 29 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3803T>A	p.Ile1268Asn	missense_variant, splice_region_variant	Exon 32 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3758T>A	p.Ile1253Asn	missense_variant, splice_region_variant	Exon 31 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1640T>A	p.Ile547Asn	missense_variant, splice_region_variant	Exon 13 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1130T>A	p.Ile377Asn	missense_variant, splice_region_variant	Exon 10 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.737T>A	p.Ile246Asn	missense_variant, splice_region_variant	Exon 8 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245990 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 41 AN: 1452788 Hom.: 0 Cov.: 30 AF XY: 0.0000236 AC XY: 17 AN XY: 721196

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.0000500

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Apr 08, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also denoted as p.I1262N due to alternative nomenclature; This variant is associated with the following publications: (PMID: 29482223, 27391121) -

Jun 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1253 of the ITPR1 protein (p.Ile1253Asn). This variant is present in population databases (rs773030719, gnomAD 0.009%). This missense change has been observed in individual(s) with autosomal dominant ITPR1-related conditions (PMID: 27391121, 29482223). This variant is also known as c.3785T>A (p.I1262N). ClinVar contains an entry for this variant (Variation ID: 447586). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Sep 09, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gillespie syndrome Uncertain:1

Jul 29, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.6	.;.;.;.;.;.;L;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;.;.;.;.;D;.
Polyphen		0.99	.;.;.;.;.;.;D;.;.;.
Vest4		0.96
MutPred		0.79		.;.;.;.;.;.;Loss of helix (P = 0.0626);.;.;.;
MVP		0.86
MPC		2.3
ClinPred		0.94	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.36
SpliceAI score (max)		0.040		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: rs773030719; hg19: chr3-4732829; COSMIC: COSV56989559;