rs372881053

Variant names:

• chr3-4685168-G-A
• rs372881053
• NM_001378452.1:c.3664G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4685168-G-A
• chr3-4685168-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BS1_Supporting

The NM_001378452.1(ITPR1):​c.3664G>A​(p.Ala1222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,606,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.24

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 -4 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=0.061921865).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000481 (70/1454718) while in subpopulation AMR AF= 0.000203 (9/44326). AF 95% confidence interval is 0.000105. There are 0 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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.3664G>A	p.Ala1222Thr	missense_variant	Exon 30 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3619G>A	p.Ala1207Thr	missense_variant	Exon 29 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3637G>A	p.Ala1213Thr	missense_variant	Exon 30 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 29 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3664G>A	p.Ala1222Thr	missense_variant	Exon 30 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3637G>A	p.Ala1213Thr	missense_variant	Exon 30 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3637G>A	p.Ala1213Thr	missense_variant	Exon 30 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3619G>A	p.Ala1207Thr	missense_variant	Exon 29 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3619G>A	p.Ala1207Thr	missense_variant	Exon 29 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 27 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3637G>A	p.Ala1213Thr	missense_variant	Exon 30 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 29 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1474G>A	p.Ala492Thr	missense_variant	Exon 11 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.964G>A	p.Ala322Thr	missense_variant	Exon 8 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.571G>A	p.Ala191Thr	missense_variant	Exon 6 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000837 AC: 20 AN: 238972 Hom.: 0 AF XY: 0.0000616 AC XY: 8 AN XY: 129970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000820

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000481 AC: 70 AN: 1454718 Hom.: 0 Cov.: 31 AF XY: 0.0000359 AC XY: 26 AN XY: 723486

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000470

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74390

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000582 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000744 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Nov 17, 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 22, 2023

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 threonine, which is neutral and polar, at codon 1198 of the ITPR1 protein (p.Ala1198Thr). This variant is present in population databases (rs372881053, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447584). 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. 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

Feb 10, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3592G>A (p.A1198T) alteration is located in exon 29 (coding exon 27) of the ITPR1 gene. This alteration results from a G to A substitution at nucleotide position 3592, causing the alanine (A) at amino acid position 1198 to be replaced by a threonine (T). 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	0.066
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.54
DEOGEN2	Uncertain	0.53	.;.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-1.7	.;.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	1.3	N;N;.;N;.;.;.;.;N;.
REVEL	Benign	0.28
Sift	Benign	1.0	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.95	T;T;.;T;.;.;.;.;T;.
Polyphen		0.0010	.;.;.;.;.;.;B;.;.;.
Vest4		0.20
MVP		0.21
MPC		0.70
ClinPred		0.038	T
GERP RS		4.4
Varity_R		0.032
gMVP		0.081

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: rs372881053; hg19: chr3-4726852; COSMIC: COSV56982426;