chr3-4800592-G-A

Variant names:

• chr3-4800592-G-A
• rs201144431
• NM_001378452.1:c.7099G>A

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.7099G>A​(p.Ala2367Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000776 in 1,613,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (1 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 9.52

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 -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=0.10317597).
• BP6: Variant 3-4800592-G-A is Benign according to our data. Variant chr3-4800592-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 345760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000677 (103/152214) while in subpopulation NFE AF= 0.00113 (77/68044). AF 95% confidence interval is 0.000928. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7099G>A	p.Ala2367Thr	missense_variant	Exon 54 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.7054G>A	p.Ala2352Thr	missense_variant	Exon 53 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.6955G>A	p.Ala2319Thr	missense_variant	Exon 51 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.6910G>A	p.Ala2304Thr	missense_variant	Exon 50 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7099G>A	p.Ala2367Thr	missense_variant	Exon 54 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7075G>A	p.Ala2359Thr	missense_variant	Exon 54 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7072G>A	p.Ala2358Thr	missense_variant	Exon 54 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7057G>A	p.Ala2353Thr	missense_variant	Exon 53 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7054G>A	p.Ala2352Thr	missense_variant	Exon 53 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7027G>A	p.Ala2343Thr	missense_variant	Exon 51 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6955G>A	p.Ala2319Thr	missense_variant	Exon 51 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6910G>A	p.Ala2304Thr	missense_variant	Exon 50 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4861G>A	p.Ala1621Thr	missense_variant	Exon 34 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4276G>A	p.Ala1426Thr	missense_variant	Exon 31 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4039G>A	p.Ala1347Thr	missense_variant	Exon 31 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000823 AC: 205 AN: 249024 Hom.: 0 AF XY: 0.000829 AC XY: 112 AN XY: 135098

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000786 AC: 1149 AN: 1461498 Hom.: 1 Cov.: 32 AF XY: 0.000781 AC XY: 568 AN XY: 727050

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.000904

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000699 AC XY: 52 AN XY: 74354

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00121 Hom.: 1

Bravo AF: 0.000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.000819 AC: 99

EpiCase AF: 0.000982

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ITPR1: PP3 -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as maternally inherited variant in individual with autism spectrum disorder; however, additional clinical information was not provided and information regarding parental phenotype was not available (Guo et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32859249, 30564305, 29232918) -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 16, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

not specified Benign:1

Nov 07, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ITPR1-related disorder Benign:1

Jun 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant cerebellar ataxia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.88	.;.;.;.;.;.;L;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.7	N;N;.;N;.;.;.;.;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.35	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.52	T;T;.;T;.;.;.;.;T;.
Polyphen		0.70	.;.;.;.;.;.;P;.;.;.
Vest4		0.59
MVP		0.65
MPC		1.0
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.25
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201144431; hg19: chr3-4842276; COSMIC: COSV56967731;