rs372433483

Variant names:

• chr3-4818224-C-G
• rs372433483
• NM_001378452.1:c.8010C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-4818224-C-G
• chr3-4818224-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001378452.1(ITPR1):​c.8010C>G​(p.Tyr2670*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y2670Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.63
• 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.8010C>G	p.Tyr2670*	stop_gained	Exon 60 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.8010C>G	p.Tyr2670*	stop_gained	Exon 60 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7986C>G	p.Tyr2662*	stop_gained	Exon 60 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7983C>G	p.Tyr2661*	stop_gained	Exon 60 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7968C>G	p.Tyr2656*	stop_gained	Exon 59 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7965C>G	p.Tyr2655*	stop_gained	Exon 59 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7938C>G	p.Tyr2646*	stop_gained	Exon 57 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7866C>G	p.Tyr2622*	stop_gained	Exon 57 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7821C>G	p.Tyr2607*	stop_gained	Exon 56 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5772C>G	p.Tyr1924*	stop_gained	Exon 40 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.5187C>G	p.Tyr1729*	stop_gained	Exon 37 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4950C>G	p.Tyr1650*	stop_gained	Exon 37 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418088 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 699592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32922

American (AMR) AF: 0.00 AC: 0 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 38854

South Asian (SAS) AF: 0.00 AC: 0 AN: 82388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078588

Other (OTH) AF: 0.00 AC: 0 AN: 58066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.27	N
PhyloP100		-2.6
Vest4		0.95
GERP RS		0.087
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs372433483; hg19: chr3-4859908;