chr3-4658161-G-A

Position:

• chr3-4658161-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001378452.1(ITPR1):​c.1034G>A​(p.Arg345Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B: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]

ITPR1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 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). GenCC has associacion of 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=0.022101134).
• BP6: Variant 3-4658161-G-A is Benign according to our data. Variant chr3-4658161-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586058.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.1034G>A	p.Arg345Gln	missense_variant	13/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.989G>A	p.Arg330Gln	missense_variant	12/61		NP_001161744.1
ITPR1	NM_001099952.4	c.1034G>A	p.Arg345Gln	missense_variant	13/59		NP_001093422.2
ITPR1	NM_002222.7	c.989G>A	p.Arg330Gln	missense_variant	12/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.1034G>A	p.Arg345Gln	missense_variant	13/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1034G>A	p.Arg345Gln	missense_variant	13/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1034G>A	p.Arg345Gln	missense_variant	13/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.989G>A	p.Arg330Gln	missense_variant	12/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.989G>A	p.Arg330Gln	missense_variant	12/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.989G>A	p.Arg330Gln	missense_variant	10/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1034G>A	p.Arg345Gln	missense_variant	13/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.989G>A	p.Arg330Gln	missense_variant	12/58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 41 AN: 248808 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 134984

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000890 AC: 130 AN: 1460976 Hom.: 0 Cov.: 31 AF XY: 0.0000977 AC XY: 71 AN XY: 726758

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.000162 AC XY: 12 AN XY: 74260

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	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; This variant is associated with the following publications: (PMID: 27535533) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -

Autosomal dominant cerebellar ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.045
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N;N;N;N;.;.;.;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.11	T;T;T;T;.;.;.;.;T
Sift4G	Benign	0.11	T;T;.;T;.;.;.;.;T
Polyphen		0.031	.;.;.;.;.;.;B;.;.
Vest4		0.17
MVP		0.87
MPC		0.84
ClinPred		0.045	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201804963; hg19: chr3-4699845;