3-4693543-C-G

Variant names:

• chr3-4693543-C-G
• rs763239856
• NM_001378452.1:c.4083C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378452.1(ITPR1):​c.4083C>G​(p.Phe1361Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.4083C>G	p.Phe1361Leu	missense_variant	Exon 33 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4038C>G	p.Phe1346Leu	missense_variant	Exon 32 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.4056C>G	p.Phe1352Leu	missense_variant	Exon 33 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.4011C>G	p.Phe1337Leu	missense_variant	Exon 32 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4083C>G	p.Phe1361Leu	missense_variant	Exon 33 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4056C>G	p.Phe1352Leu	missense_variant	Exon 33 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4056C>G	p.Phe1352Leu	missense_variant	Exon 33 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4038C>G	p.Phe1346Leu	missense_variant	Exon 32 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4038C>G	p.Phe1346Leu	missense_variant	Exon 32 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4011C>G	p.Phe1337Leu	missense_variant	Exon 30 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4056C>G	p.Phe1352Leu	missense_variant	Exon 33 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4011C>G	p.Phe1337Leu	missense_variant	Exon 32 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.1893C>G	p.Phe631Leu	missense_variant	Exon 14 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1383C>G	p.Phe461Leu	missense_variant	Exon 11 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.990C>G	p.Phe330Leu	missense_variant	Exon 9 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249286 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111822

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1337 of the ITPR1 protein (p.Phe1337Leu). This variant is present in population databases (rs763239856, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITPR1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;M;.;.;.
PhyloP100		3.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.8	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.76
Sift	Benign	0.12	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.17	T;T;.;T;.;.;.;.;T;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.65
MutPred		0.69		.;.;.;.;.;.;Gain of MoRF binding (P = 0.2545);.;.;.;
MVP		0.84
MPC		1.9
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.65
gMVP		0.74
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763239856; hg19: chr3-4735227;