NM_001378452.1:c.-2A>T

Variant names:

• chr3-4516490-A-T
• rs369723935
• NM_001378452.1:c.-2A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001378452.1(ITPR1):​c.-2A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 1,551,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.-2A>T		5_prime_UTR_variant	Exon 3 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.-2A>T		5_prime_UTR_variant	Exon 3 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.-2A>T		5_prime_UTR_variant	Exon 3 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.-2A>T		5_prime_UTR_variant	Exon 3 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.-2A>T		5_prime_UTR_variant	Exon 3 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.-2A>T		5_prime_UTR_variant	Exon 3 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.-2A>T		5_prime_UTR_variant	Exon 3 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.-2A>T		5_prime_UTR_variant	Exon 3 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.-2A>T		5_prime_UTR_variant	Exon 3 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.-2A>T		5_prime_UTR_variant	Exon 1 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.-2A>T		5_prime_UTR_variant	Exon 3 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.-2A>T		5_prime_UTR_variant	Exon 3 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000901 AC: 2 AN: 221952 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.00000953

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1399192 Hom.: 0 Cov.: 25 AF XY: 0.00000574 AC XY: 4 AN XY: 696932

African (AFR) AF: 0.00 AC: 0 AN: 30928

American (AMR) AF: 0.00 AC: 0 AN: 38316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25356

East Asian (EAS) AF: 0.00 AC: 0 AN: 37480

South Asian (SAS) AF: 0.00 AC: 0 AN: 77460

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000466 AC: 5 AN: 1072600

Other (OTH) AF: 0.0000172 AC: 1 AN: 58186

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000305 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		1.2
PromoterAI		-0.0017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs369723935; hg19: chr3-4558174;