rs200335594

Variant names:

• chr3-4670726-T-C
• rs200335594
• NM_001378452.1:c.2007-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.2007-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,570,614 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (9 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.00005515
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.343
• Publications: 1 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-4670726-T-C is Benign according to our data. Variant chr3-4670726-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00142 (216/152358) while in subpopulation NFE AF = 0.00262 (178/68028). AF 95% confidence interval is 0.0023. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.2007-3T>C		splice_region intron	N/A	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.1962-3T>C		splice_region intron	N/A	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.2007-3T>C		splice_region intron	N/A	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.2007-3T>C		splice_region intron	N/A	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.2007-3T>C		splice_region intron	N/A	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.2007-3T>C		splice_region intron	N/A	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00100 AC: 198 AN: 198044 AF XY: 0.00107

Gnomad AFR exome AF: 0.000338

Gnomad AMR exome AF: 0.000356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000209

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00224 AC: 3183 AN: 1418256 Hom.: 9 Cov.: 26 AF XY: 0.00213 AC XY: 1494 AN XY: 702570

African (AFR) AF: 0.000368 AC: 12 AN: 32600

American (AMR) AF: 0.000414 AC: 16 AN: 38630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25486

East Asian (EAS) AF: 0.00 AC: 0 AN: 38542

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81326

European-Finnish (FIN) AF: 0.000524 AC: 27 AN: 51550

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5650

European-Non Finnish (NFE) AF: 0.00282 AC: 3061 AN: 1085480

Other (OTH) AF: 0.00110 AC: 65 AN: 58992

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.00123 AC XY: 92 AN XY: 74510

African (AFR) AF: 0.000313 AC: 13 AN: 41584

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00147

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Intellectual disability (1)
-	-	1	ITPR1-related disorder (1)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.0
DANN	Benign	0.63
PhyloP100		0.34
PromoterAI		-0.0026	Neutral
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.010		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: rs200335594; hg19: chr3-4712410;