3-4675127-A-G

Variant names:

• chr3-4675127-A-G
• rs2306877
• NM_001378452.1:c.2658A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001378452.1(ITPR1):​c.2658A>G​(p.Leu886Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,946 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. Synonymous variant affecting the same amino acid position (i.e. L886L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 23 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2658A>G	p.Leu886Leu	synonymous_variant	Exon 23 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2613A>G	p.Leu871Leu	synonymous_variant	Exon 22 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.2658A>G	p.Leu886Leu	synonymous_variant	Exon 23 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.2613A>G	p.Leu871Leu	synonymous_variant	Exon 22 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2658A>G	p.Leu886Leu	synonymous_variant	Exon 23 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2658A>G	p.Leu886Leu	synonymous_variant	Exon 23 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2658A>G	p.Leu886Leu	synonymous_variant	Exon 23 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2613A>G	p.Leu871Leu	synonymous_variant	Exon 22 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2613A>G	p.Leu871Leu	synonymous_variant	Exon 22 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2613A>G	p.Leu871Leu	synonymous_variant	Exon 20 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2658A>G	p.Leu886Leu	synonymous_variant	Exon 23 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2613A>G	p.Leu871Leu	synonymous_variant	Exon 22 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.495A>G	p.Leu165Leu	synonymous_variant	Exon 4 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.-16A>G		upstream_gene_variant				ENSP00000498149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454946 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724262

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106108

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.88
DANN	Benign	0.59
PhyloP100		-1.5
PromoterAI		0.00040	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2306877; hg19: chr3-4716811;