NM_001378452.1:c.-16-56T>C

Variant names:

• chr3-4516420-T-C
• rs9829878
• NM_001378452.1:c.-16-56T>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.-16-56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 946,352 control chromosomes in the GnomAD database, including 1,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (710 hom., cov: 33)
  • Exomes 𝑓: 0.014 (318 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.85
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-4516420-T-C is Benign according to our data. Variant chr3-4516420-T-C is described in ClinVar as Benign. ClinVar VariationId is 1269017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.-16-56T>C		intron	N/A	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.-16-56T>C		intron	N/A	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.-16-56T>C		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.-16-56T>C		intron	N/A	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.-16-56T>C		intron	N/A	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.-16-56T>C		intron	N/A	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8826 AN: 152178 Hom.: 701 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00692

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0430

GnomAD4 exome AF: 0.0137 AC: 10906 AN: 794056 Hom.: 318 AF XY: 0.0134 AC XY: 5455 AN XY: 408470

African (AFR) AF: 0.170 AC: 2735 AN: 16124

American (AMR) AF: 0.0160 AC: 329 AN: 20612

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 238 AN: 18210

East Asian (EAS) AF: 0.00296 AC: 90 AN: 30356

South Asian (SAS) AF: 0.0109 AC: 575 AN: 52776

European-Finnish (FIN) AF: 0.00425 AC: 213 AN: 50064

Middle Eastern (MID) AF: 0.0284 AC: 122 AN: 4290

European-Non Finnish (NFE) AF: 0.0103 AC: 5841 AN: 564682

Other (OTH) AF: 0.0207 AC: 763 AN: 36942

GnomAD4 genome AF: 0.0582 AC: 8859 AN: 152296 Hom.: 710 Cov.: 33 AF XY: 0.0565 AC XY: 4207 AN XY: 74474

African (AFR) AF: 0.178 AC: 7403 AN: 41530

American (AMR) AF: 0.0291 AC: 445 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00674 AC: 35 AN: 5192

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4826

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10618

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 757 AN: 68036

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0382 Hom.: 164

Bravo AF: 0.0642

Asia WGS AF: 0.0230 AC: 80 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.61
CADD	Benign	0.18
DANN	Benign	0.87
PhyloP100		-2.8
PromoterAI		-0.013	Neutral
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: rs9829878; hg19: chr3-4558104;