NM_001378452.1:c.1606C>A

Variant names:

• chr3-4665189-C-A
• rs1553681680
• NM_001378452.1:c.1606C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378452.1(ITPR1):​c.1606C>A​(p.Leu536Ile) 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 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L536F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.1606C>A	p.Leu536Ile	missense_variant	Exon 17 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.1561C>A	p.Leu521Ile	missense_variant	Exon 16 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.1606C>A	p.Leu536Ile	missense_variant	Exon 17 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.1561C>A	p.Leu521Ile	missense_variant	Exon 16 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.1606C>A	p.Leu536Ile	missense_variant	Exon 17 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.1606C>A	p.Leu536Ile	missense_variant	Exon 17 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.1606C>A	p.Leu536Ile	missense_variant	Exon 17 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.1561C>A	p.Leu521Ile	missense_variant	Exon 16 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.1561C>A	p.Leu521Ile	missense_variant	Exon 16 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.1561C>A	p.Leu521Ile	missense_variant	Exon 14 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.1606C>A	p.Leu536Ile	missense_variant	Exon 17 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.1561C>A	p.Leu521Ile	missense_variant	Exon 16 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727120

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: 1111826

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;.;.;.;.;.;D;.;.
Eigen	Benign	0.073
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;M;.;.
PhyloP100		0.91
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N;N;N;N;.;.;.;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.042	D;D;D;D;.;.;.;.;D
Sift4G	Benign	0.10	T;T;.;T;.;.;.;.;T
Polyphen		0.26	.;.;.;.;.;.;B;.;.
Vest4		0.53
MutPred		0.62		Gain of catalytic residue at L541 (P = 0.0291);.;Gain of catalytic residue at L541 (P = 0.0291);.;Gain of catalytic residue at L541 (P = 0.0291);.;Gain of catalytic residue at L541 (P = 0.0291);.;.;
MVP		0.65
MPC		1.7
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.28
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs1553681680; hg19: chr3-4706873; COSMIC: COSV108137458;