rs371726673

Positions:

• chr3-4814491-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BS1_Supporting

The NM_001378452.1(ITPR1):​c.7630G>A​(p.Val2544Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,612,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.67

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]

ENSG00000235978 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 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). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. GenCC has associacion of the 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=0.31205642).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000066 (10/151628) while in subpopulation NFE AF= 0.000132 (9/67984). AF 95% confidence interval is 0.0000681. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. 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/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7630G>A	p.Val2544Ile	missense_variant	58/62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7630G>A	p.Val2544Ile	missense_variant	58/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7606G>A	p.Val2536Ile	missense_variant	58/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7603G>A	p.Val2535Ile	missense_variant	58/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7588G>A	p.Val2530Ile	missense_variant	57/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7585G>A	p.Val2529Ile	missense_variant	57/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7558G>A	p.Val2520Ile	missense_variant	55/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7486G>A	p.Val2496Ile	missense_variant	55/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7441G>A	p.Val2481Ile	missense_variant	54/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5392G>A	p.Val1798Ile	missense_variant	38/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4807G>A	p.Val1603Ile	missense_variant	35/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4570G>A	p.Val1524Ile	missense_variant	35/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000660 AC: 10 AN: 151628 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249294 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461158 Hom.: 0 Cov.: 30 AF XY: 0.0000385 AC XY: 28 AN XY: 726884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000423

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000660 AC: 10 AN: 151628 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73988

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ITPR1: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 15, 2023	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITPR1 protein function. ClinVar contains an entry for this variant (Variation ID: 586055). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. This variant is present in population databases (rs371726673, gnomAD 0.007%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2481 of the ITPR1 protein (p.Val2481Ile). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 02, 2023

Variant summary: ITPR1 c.7441G>A (p.Val2481Ile) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 (i.e. in 8 carriers) in 249294 control chromosomes (gnomAD v2.1 exomes dataset). The available data on variant occurrences in the general population are insufficient to allow clear conclusions about variant significance, although it suggests that the variant is likely not associated with a high penetrance, early onset disease phenotype. To our knowledge, no occurrence of c.7441G>A in individuals affected with Spinocerebellar Ataxia 29 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

The c.7441G>A (p.V2481I) alteration is located in exon 54 (coding exon 52) of the ITPR1 gene. This alteration results from a G to A substitution at nucleotide position 7441, causing the valine (V) at amino acid position 2481 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	.;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.077
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	0.49	.;.;.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.58	N;N;.;N;.;N;.;.;.;N;.
REVEL	Uncertain	0.48
Sift	Benign	0.41	T;T;.;T;.;T;.;.;.;T;.
Sift4G	Benign	0.59	T;T;.;T;.;T;.;.;.;T;.
Polyphen		0.23, 0.039	.;.;.;.;.;B;.;B;.;.;.
Vest4		0.34
MVP		0.36
MPC		0.72
ClinPred		0.24	T
GERP RS		5.1
Varity_R		0.075
gMVP		0.92

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: rs371726673; hg19: chr3-4856175;