3-4710317-C-T

Variant names:

• chr3-4710317-C-T
• rs41304179
• NM_001378452.1:c.4843-8C>T

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.4843-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,536,034 control chromosomes in the GnomAD database, including 7 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 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: ITPR1 NM_001378452.1 splice_region, intron
• Scores: Splicing: ADA: 0.00001639
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0270
• Publications: 2 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)

LOC124906210 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-4710317-C-T is Benign according to our data. Variant chr3-4710317-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 447591.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 = 0.00112 (171/152316) while in subpopulation NFE AF = 0.00204 (139/68038). AF 95% confidence interval is 0.00177. There are 0 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.4843-8C>T		splice_region intron	N/A	NP_001365381.1
	ITPR1	NM_001168272.2		c.4798-8C>T		splice_region intron	N/A	NP_001161744.1
	ITPR1	NM_001099952.4		c.4816-8C>T		splice_region intron	N/A	NP_001093422.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.4843-8C>T		splice_region intron	N/A	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.4816-8C>T		splice_region intron	N/A	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.4816-8C>T		splice_region intron	N/A	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000871 AC: 148 AN: 169962 AF XY: 0.000821

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000173

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.00184 AC: 2540 AN: 1383718 Hom.: 7 Cov.: 30 AF XY: 0.00171 AC XY: 1160 AN XY: 679370

African (AFR) AF: 0.000253 AC: 8 AN: 31582

American (AMR) AF: 0.000785 AC: 28 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24474

East Asian (EAS) AF: 0.00 AC: 0 AN: 36520

South Asian (SAS) AF: 0.000321 AC: 25 AN: 77882

European-Finnish (FIN) AF: 0.000160 AC: 8 AN: 49948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4768

European-Non Finnish (NFE) AF: 0.00225 AC: 2397 AN: 1065802

Other (OTH) AF: 0.00130 AC: 74 AN: 57088

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74482

African (AFR) AF: 0.000361 AC: 15 AN: 41550

American (AMR) AF: 0.000914 AC: 14 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00204 AC: 139 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00105

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Intellectual disability (1)
-	-	1	ITPR1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.49
PhyloP100		-0.027
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs41304179; hg19: chr3-4752001;