rs556943368

Variant names:

• chr3-4691227-C-A
• NM_001378452.1:c.3912C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4691227-C-A
• chr3-4691227-C-G
• chr3-4691227-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001378452.1(ITPR1):​c.3912C>A​(p.His1304Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.3912C>A	p.His1304Gln	missense_variant	Exon 32 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.3867C>A	p.His1289Gln	missense_variant	Exon 31 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.3885C>A	p.His1295Gln	missense_variant	Exon 32 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.3840C>A	p.His1280Gln	missense_variant	Exon 31 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.3912C>A	p.His1304Gln	missense_variant	Exon 32 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.3885C>A	p.His1295Gln	missense_variant	Exon 32 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.3885C>A	p.His1295Gln	missense_variant	Exon 32 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.3867C>A	p.His1289Gln	missense_variant	Exon 31 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.3867C>A	p.His1289Gln	missense_variant	Exon 31 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.3840C>A	p.His1280Gln	missense_variant	Exon 29 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.3885C>A	p.His1295Gln	missense_variant	Exon 32 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.3840C>A	p.His1280Gln	missense_variant	Exon 31 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1722C>A	p.His574Gln	missense_variant	Exon 13 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1212C>A	p.His404Gln	missense_variant	Exon 10 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.819C>A	p.His273Gln	missense_variant	Exon 8 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 07, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.80
Sift	Benign	0.084	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.11	T;T;.;T;.;.;.;.;T;.
Polyphen		0.99	.;.;.;.;.;.;D;.;.;.
Vest4		0.92
MutPred		0.69		.;.;.;.;.;.;Loss of sheet (P = 0.1158);.;.;.;
MVP		0.93
MPC		1.8
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.64
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-4732911;