3-4814521-G-C

Variant names:

• chr3-4814521-G-C
• rs752281590
• NM_001378452.1:c.7660G>C

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001378452.1(ITPR1):​c.7660G>C​(p.Gly2554Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2554V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 Pathogenic. Variant got 21 ACMG points.

• PS1: Transcript NM_001378452.1 (ITPR1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-4814522-G-T is described in Lovd as [Likely_pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 3-4814521-G-C is Pathogenic according to our data. Variant chr3-4814521-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 235923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4814521-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7660G>C	p.Gly2554Arg	missense_variant	Exon 58 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7660G>C	p.Gly2554Arg	missense_variant	Exon 58 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7636G>C	p.Gly2546Arg	missense_variant	Exon 58 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7633G>C	p.Gly2545Arg	missense_variant	Exon 58 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7618G>C	p.Gly2540Arg	missense_variant	Exon 57 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7615G>C	p.Gly2539Arg	missense_variant	Exon 57 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7588G>C	p.Gly2530Arg	missense_variant	Exon 55 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7516G>C	p.Gly2506Arg	missense_variant	Exon 55 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7471G>C	p.Gly2491Arg	missense_variant	Exon 54 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5422G>C	p.Gly1808Arg	missense_variant	Exon 38 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4837G>C	p.Gly1613Arg	missense_variant	Exon 35 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4600G>C	p.Gly1534Arg	missense_variant	Exon 35 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31785789, 27108798) -

Gillespie syndrome Pathogenic:1

Jul 20, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;.;.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;.;D;.;D;.;.;.;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.
Vest4		0.99
MutPred		0.81		.;.;.;.;.;.;.;Gain of solvent accessibility (P = 6e-04);.;.;.;
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.99

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: rs752281590; hg19: chr3-4856205;