rs943946433

Variant names:

• chr3-4699840-C-G
• rs943946433
• NM_001378452.1:c.4435C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-4699840-C-G
• chr3-4699840-C-T

Variant summary

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

The NM_001378452.1(ITPR1):​c.4435C>G​(p.His1479Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,596 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. H1479Y) 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: 7.84
• 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.4435C>G	p.His1479Asp	missense_variant	Exon 35 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.4390C>G	p.His1464Asp	missense_variant	Exon 34 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.4408C>G	p.His1470Asp	missense_variant	Exon 35 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.4363C>G	p.His1455Asp	missense_variant	Exon 34 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.4435C>G	p.His1479Asp	missense_variant	Exon 35 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.4408C>G	p.His1470Asp	missense_variant	Exon 35 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.4408C>G	p.His1470Asp	missense_variant	Exon 35 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.4390C>G	p.His1464Asp	missense_variant	Exon 34 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.4390C>G	p.His1464Asp	missense_variant	Exon 34 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.4363C>G	p.His1455Asp	missense_variant	Exon 32 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.4408C>G	p.His1470Asp	missense_variant	Exon 35 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.4363C>G	p.His1455Asp	missense_variant	Exon 34 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.2245C>G	p.His749Asp	missense_variant	Exon 16 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.1735C>G	p.His579Asp	missense_variant	Exon 13 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.1342C>G	p.His448Asp	missense_variant	Exon 11 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461596 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;.;.;.;.;D;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;M;.;.;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.1	D;D;.;D;.;.;.;.;D;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.17	T;T;.;T;.;.;.;.;T;.;.
Sift4G	Benign	0.23	T;T;.;T;.;.;.;.;T;.;.
Polyphen		0.90	.;.;.;.;.;.;P;.;.;.;.
Vest4		0.89
MutPred		0.17		.;.;.;.;.;.;Gain of ubiquitination at K1478 (P = 0.0671);.;.;.;.;
MVP		0.81
MPC		2.0
ClinPred		0.96	D
GERP RS		5.7
PromoterAI		-0.049	Neutral
Varity_R		0.59
gMVP		0.56
Mutation Taster		=11/89	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: rs943946433; hg19: chr3-4741524;