3-4645609-G-T

Variant names:

• chr3-4645609-G-T
• NM_001378452.1:c.736G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001378452.1(ITPR1):​c.736G>T​(p.Glu246*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,310 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.89

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 Pathogenic. Variant got 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.736G>T	p.Glu246*	stop_gained	Exon 10 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.736G>T	p.Glu246*	stop_gained	Exon 8 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.736G>T	p.Glu246*	stop_gained	Exon 10 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461310 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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	0.66
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.98
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr3-4687293;