rs373694009

Variant names:

• chr3-4670833-G-A
• rs373694009
• NM_001378452.1:c.2111G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4670833-G-A
• chr3-4670833-G-C
• chr3-4670833-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.2111G>A​(p.Ser704Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,610,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.60

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 -1 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=0.1497168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2111G>A	p.Ser704Asn	missense_variant	Exon 20 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2066G>A	p.Ser689Asn	missense_variant	Exon 19 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2111G>A	p.Ser704Asn	missense_variant	Exon 20 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2066G>A	p.Ser689Asn	missense_variant	Exon 19 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2111G>A	p.Ser704Asn	missense_variant	Exon 20 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2111G>A	p.Ser704Asn	missense_variant	Exon 20 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2111G>A	p.Ser704Asn	missense_variant	Exon 20 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2066G>A	p.Ser689Asn	missense_variant	Exon 19 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2066G>A	p.Ser689Asn	missense_variant	Exon 19 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2066G>A	p.Ser689Asn	missense_variant	Exon 17 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2111G>A	p.Ser704Asn	missense_variant	Exon 20 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2066G>A	p.Ser689Asn	missense_variant	Exon 19 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.-53G>A		upstream_gene_variant				ENSP00000497872.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000205 AC: 5 AN: 243632 Hom.: 0 AF XY: 0.0000303 AC XY: 4 AN XY: 132002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

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: 0.0000362

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1458488 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 725126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

Gnomad4 AFR AF: 0.0000241

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: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Mar 04, 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; Has not been previously published as pathogenic or benign to our knowledge -

Oct 18, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 689 of the ITPR1 protein (p.Ser689Asn). ClinVar contains an entry for this variant (Variation ID: 586043). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.35	.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.44	N;.;.;.;.;.;N;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.45	N;N;N;N;.;.;.;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.40	T;T;T;T;.;.;.;.;T
Sift4G	Benign	0.64	T;T;.;T;.;.;.;.;T
Polyphen		0.0010	.;.;.;.;.;.;B;.;.
Vest4		0.12
MutPred		0.40		Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);.;.;
MVP		0.68
MPC		0.67
ClinPred		0.095	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.35

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: rs373694009; hg19: chr3-4712517;