3-4675201-C-T

Variant names:

• chr3-4675201-C-T
• rs201519806
• NM_001378452.1:c.2732C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_001378452.1(ITPR1):​c.2732C>T​(p.Ala911Val) variant causes a missense change. The variant allele was found at a frequency of 0.000323 in 1,611,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 4.45

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 Likely_benign. Variant got -6 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07862571).
• BP6: Variant 3-4675201-C-T is Benign according to our data. Variant chr3-4675201-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345716.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000408 (62/152070) while in subpopulation NFE AF= 0.00072 (49/68020). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2732C>T	p.Ala911Val	missense_variant	Exon 23 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2687C>T	p.Ala896Val	missense_variant	Exon 22 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2732C>T	p.Ala911Val	missense_variant	Exon 23 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2687C>T	p.Ala896Val	missense_variant	Exon 22 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2732C>T	p.Ala911Val	missense_variant	Exon 23 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2732C>T	p.Ala911Val	missense_variant	Exon 23 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2732C>T	p.Ala911Val	missense_variant	Exon 23 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2687C>T	p.Ala896Val	missense_variant	Exon 22 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2687C>T	p.Ala896Val	missense_variant	Exon 22 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2687C>T	p.Ala896Val	missense_variant	Exon 20 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2732C>T	p.Ala911Val	missense_variant	Exon 23 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2687C>T	p.Ala896Val	missense_variant	Exon 22 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.569C>T	p.Ala190Val	missense_variant	Exon 4 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.59C>T	p.Ala20Val	missense_variant	Exon 1 of 39			ENSP00000498149.1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000368 AC: 91 AN: 247512 Hom.: 0 AF XY: 0.000380 AC XY: 51 AN XY: 134292

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000675

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1459730 Hom.: 0 Cov.: 30 AF XY: 0.000340 AC XY: 247 AN XY: 726088

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000363

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000408 AC: 62 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74264

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000314 AC: 38

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Oct 26, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29925855, 29232918, 30778698) -

Jul 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 896 of the ITPR1 protein (p.Ala896Val). This variant is present in population databases (rs201519806, gnomAD 0.06%). This missense change has been observed in individual(s) with hereditary spastic pariplegia (PMID: 30778698). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 345716). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ITPR1 protein function with a negative predictive value of 95%. 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. -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2687C>T (p.A896V) alteration is located in exon 22 (coding exon 20) of the ITPR1 gene. This alteration results from a C to T substitution at nucleotide position 2687, causing the alanine (A) at amino acid position 896 to be replaced by a valine (V). This variant is unlikely to be causative of spinocerebellar ataxia; however, its contribution to the development of Gillespie syndrome is uncertain. Based on data from the Genome Aggregation Database (gnomAD) database, the ITPR1 c.2687C>T alteration was observed in 0.04% (103/278904) of total alleles studied, with a frequency of 0.07% (86/127962) in the European (non-Finnish) subpopulation. This variant was identified in two families with hereditary spastic paraplegia (Elert-Dobkowska, 2019). This amino acid position is not well conserved in available vertebrate species. The p.A896V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 29 Benign:1

Feb 09, 2018

Schule lab, Hertie Institute for Clinical Brain Research

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Autosomal dominant cerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.14	N;.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.5	N;N;N;N;.;.;.;.;N;.
REVEL	Benign	0.21
Sift	Benign	0.44	T;T;T;T;.;.;.;.;T;.
Sift4G	Benign	0.37	T;T;.;T;.;.;.;.;T;.
Polyphen		0.69	.;.;.;.;.;.;P;.;.;.
Vest4		0.27
MVP		0.54
MPC		0.76
ClinPred		0.029	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201519806; hg19: chr3-4716885; COSMIC: COSV56986903; COSMIC: COSV56986903;