rs304075

Variant names:

• chr3-4493746-G-A
• rs304075
• NM_001378452.1:c.-93+141G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-4493746-G-A
• chr3-4493746-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.-93+141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 152,416 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (92 hom., cov: 32)
  • Exomes 𝑓: 0.052 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.458
• 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: 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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0288 (4392/152282) while in subpopulation NFE AF = 0.0464 (3153/68016). AF 95% confidence interval is 0.045. There are 92 homozygotes in GnomAd4. There are 2017 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.-93+141G>A		intron	N/A	NP_001365381.1
	ITPR1	NM_001168272.2		c.-93+141G>A		intron	N/A	NP_001161744.1
	ITPR1	NM_001099952.4		c.-93+141G>A		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.-93+141G>A		intron	N/A	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.-93+141G>A		intron	N/A	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.-93+141G>A		intron	N/A	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4390 AN: 152164 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0464

Gnomad OTH AF: 0.0259

GnomAD4 exome AF: 0.0522 AC: 7 AN: 134 Hom.: 0 AF XY: 0.0463 AC XY: 5 AN XY: 108

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0648 AC: 7 AN: 108

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.0288 AC: 4392 AN: 152282 Hom.: 92 Cov.: 32 AF XY: 0.0271 AC XY: 2017 AN XY: 74468

African (AFR) AF: 0.00946 AC: 393 AN: 41560

American (AMR) AF: 0.0220 AC: 336 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4830

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0464 AC: 3153 AN: 68016

Other (OTH) AF: 0.0256 AC: 54 AN: 2110

Alfa AF: 0.0386 Hom.: 169

Bravo AF: 0.0290

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.7
DANN	Benign	0.84
PhyloP100		-0.46
PromoterAI		0.0046	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: rs304075; hg19: chr3-4535430;