3-4787891-T-C

Variant names:

• chr3-4787891-T-C
• rs17786144
• NM_001378452.1:c.6616-56T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378452.1(ITPR1):​c.6616-56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,269,810 control chromosomes in the GnomAD database, including 9,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (643 hom., cov: 31)
  • Exomes 𝑓: 0.12 (8946 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-4787891-T-C is Benign according to our data. Variant chr3-4787891-T-C is described in ClinVar as Benign. ClinVar VariationId is 1240984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.6616-56T>C		intron	N/A	NP_001365381.1
	ITPR1	NM_001168272.2		c.6571-56T>C		intron	N/A	NP_001161744.1
	ITPR1	NM_001099952.4		c.6472-56T>C		intron	N/A	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.6616-56T>C		intron	N/A	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.6592-56T>C		intron	N/A	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.6589-56T>C		intron	N/A	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12404 AN: 151686 Hom.: 644 Cov.: 31

Gnomad AFR AF: 0.0246

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0684

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.0846

GnomAD4 exome AF: 0.117 AC: 131215 AN: 1118006 Hom.: 8946 AF XY: 0.115 AC XY: 64700 AN XY: 564900

African (AFR) AF: 0.0199 AC: 507 AN: 25532

American (AMR) AF: 0.0504 AC: 1568 AN: 31140

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2508 AN: 22958

East Asian (EAS) AF: 0.000168 AC: 6 AN: 35694

South Asian (SAS) AF: 0.0328 AC: 2286 AN: 69720

European-Finnish (FIN) AF: 0.0916 AC: 4620 AN: 50452

Middle Eastern (MID) AF: 0.0639 AC: 317 AN: 4964

European-Non Finnish (NFE) AF: 0.138 AC: 114282 AN: 828950

Other (OTH) AF: 0.105 AC: 5121 AN: 48596

GnomAD4 genome AF: 0.0817 AC: 12402 AN: 151804 Hom.: 643 Cov.: 31 AF XY: 0.0779 AC XY: 5781 AN XY: 74168

African (AFR) AF: 0.0245 AC: 1016 AN: 41398

American (AMR) AF: 0.0682 AC: 1040 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3470

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0294 AC: 141 AN: 4790

European-Finnish (FIN) AF: 0.0874 AC: 921 AN: 10538

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8566 AN: 67878

Other (OTH) AF: 0.0833 AC: 175 AN: 2102

Alfa AF: 0.112 Hom.: 1784

Bravo AF: 0.0779

Asia WGS AF: 0.0160 AC: 56 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.56
DANN	Benign	0.36
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs17786144; hg19: chr3-4829575;