3-4693723-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):c.4263C>G(p.His1421Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,612,892 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H1421H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.56

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ITPR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.009713441).
• BP6: Variant 3-4693723-C-G is Benign according to our data. Variant chr3-4693723-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 345736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00503 (766/152348) while in subpopulation AFR AF= 0.014 (582/41592). AF 95% confidence interval is 0.0131. There are 7 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.4263C>G	p.His1421Gln	missense_variant	33/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.4218C>G	p.His1406Gln	missense_variant	32/61
ITPR1	NM_001099952.4	c.4236C>G	p.His1412Gln	missense_variant	33/59
ITPR1	NM_002222.7	c.4191C>G	p.His1397Gln	missense_variant	32/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.4263C>G	p.His1421Gln	missense_variant	33/62		NM_001378452.1

Frequencies

GnomAD3 genomes AF: 0.00505 AC: 768 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00215 AC: 531 AN: 246696 Hom.: 2 AF XY: 0.00180 AC XY: 241 AN XY: 133804

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.00475

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000895

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00126 AC: 1845 AN: 1460544 Hom.: 5 Cov.: 31 AF XY: 0.00122 AC XY: 888 AN XY: 726432

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000691

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00471 AC XY: 351 AN XY: 74498

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00606

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ITPR1: PP3, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 10, 2019

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	Pathogenic	0.72
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	10
Dann	Benign	0.97
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0097	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;.;D;.;.;.;.;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.79
MutPred		0.37		.;.;.;.;.;.;Loss of catalytic residue at D1423 (P = 0.1755);.;.;.;
MVP		0.85
MPC		1.5
ClinPred		0.12	T
GERP RS		-9.2
Varity_R		0.68
gMVP		0.74

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: rs61757110; hg19: chr3-4735407;