3-4815135-G-C

Position:

• chr3-4815135-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001378452.1(ITPR1):​c.7784G>C​(p.Gly2595Ala) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.92

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 3-4815135-G-C is Pathogenic according to our data. Variant chr3-4815135-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243076.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7784G>C	p.Gly2595Ala	missense_variant	59/62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7784G>C	p.Gly2595Ala	missense_variant	59/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7760G>C	p.Gly2587Ala	missense_variant	59/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7757G>C	p.Gly2586Ala	missense_variant	59/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7742G>C	p.Gly2581Ala	missense_variant	58/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7739G>C	p.Gly2580Ala	missense_variant	58/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7712G>C	p.Gly2571Ala	missense_variant	56/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7640G>C	p.Gly2547Ala	missense_variant	56/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7595G>C	p.Gly2532Ala	missense_variant	55/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5546G>C	p.Gly1849Ala	missense_variant	39/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4961G>C	p.Gly1654Ala	missense_variant	36/39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4724G>C	p.Gly1575Ala	missense_variant	36/39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 29 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Aug 18, 2015

Likely pathogenic based on prediction scores (SIFT, MutationTaster). This de novo variant was identified in a patient with congenital ataxia who also had peripheral neuropathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;.;D;.;.;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;.;.;.;.;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.7	D;D;.;D;.;N;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;D;.;D;.;.;.;D;.;.;.;.
Polyphen		1.0	.;.;.;.;.;D;.;D;.;.;.;.;.;.
Vest4		0.96
MutPred		0.63		.;.;.;.;.;.;.;Gain of helix (P = 0.1736);.;.;.;.;.;.;
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		1.0

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: rs869312685; hg19: chr3-4856819;