chr3-4516359-A-G

Variant names:

• chr3-4516359-A-G
• rs73003291
• NM_001378452.1:c.-16-117A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.-16-117A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00844 in 556,064 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (19 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.548
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 3-4516359-A-G is Benign according to our data. Variant chr3-4516359-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1219513.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 = 0.00716 (1090/152326) while in subpopulation NFE AF = 0.0103 (701/68036). AF 95% confidence interval is 0.00967. There are 6 homozygotes in GnomAd4. There are 530 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.-16-117A>G		intron	N/A	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.-16-117A>G		intron	N/A	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.-16-117A>G		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.-16-117A>G		intron	N/A	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.-16-117A>G		intron	N/A	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.-16-117A>G		intron	N/A	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1092 AN: 152208 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00692

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00892 AC: 3603 AN: 403738 Hom.: 19 AF XY: 0.00907 AC XY: 1925 AN XY: 212332

African (AFR) AF: 0.00273 AC: 25 AN: 9170

American (AMR) AF: 0.00634 AC: 65 AN: 10260

Ashkenazi Jewish (ASJ) AF: 0.00874 AC: 109 AN: 12466

East Asian (EAS) AF: 0.00258 AC: 67 AN: 25966

South Asian (SAS) AF: 0.0100 AC: 321 AN: 31958

European-Finnish (FIN) AF: 0.00434 AC: 163 AN: 37540

Middle Eastern (MID) AF: 0.0159 AC: 37 AN: 2334

European-Non Finnish (NFE) AF: 0.0104 AC: 2593 AN: 250234

Other (OTH) AF: 0.00937 AC: 223 AN: 23810

GnomAD4 genome AF: 0.00716 AC: 1090 AN: 152326 Hom.: 6 Cov.: 33 AF XY: 0.00712 AC XY: 530 AN XY: 74488

African (AFR) AF: 0.00226 AC: 94 AN: 41552

American (AMR) AF: 0.00824 AC: 126 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00674 AC: 35 AN: 5194

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 701 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00990 Hom.: 0

Bravo AF: 0.00730

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.79
PhyloP100		0.55
PromoterAI		0.026	Neutral
Mutation Taster		=100/0	polymorphism

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: rs73003291; hg19: chr3-4558043;