chr3-4675127-A-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.2658A>C​(p.Leu886Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,605,562 control chromosomes in the GnomAD database, including 43,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5980 hom., cov: 32)
  • Exomes 𝑓: 0.21 (37154 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-4675127-A-C is Benign according to our data. Variant chr3-4675127-A-C is described in ClinVar as Benign. ClinVar VariationId is 129299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 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.2658A>C	p.Leu886Leu	synonymous	Exon 23 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.2613A>C	p.Leu871Leu	synonymous	Exon 22 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.2658A>C	p.Leu886Leu	synonymous	Exon 23 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.2658A>C	p.Leu886Leu	synonymous	Exon 23 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.2658A>C	p.Leu886Leu	synonymous	Exon 23 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.2658A>C	p.Leu886Leu	synonymous	Exon 23 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40967 AN: 151992 Hom.: 5968 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.271 AC: 67189 AN: 247978 AF XY: 0.266

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.214 AC: 310432 AN: 1453452 Hom.: 37154 Cov.: 29 AF XY: 0.217 AC XY: 157259 AN XY: 723564

African (AFR) AF: 0.374 AC: 12441 AN: 33266

American (AMR) AF: 0.402 AC: 17897 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3932 AN: 26086

East Asian (EAS) AF: 0.290 AC: 11463 AN: 39592

South Asian (SAS) AF: 0.376 AC: 32303 AN: 85830

European-Finnish (FIN) AF: 0.294 AC: 15675 AN: 53356

Middle Eastern (MID) AF: 0.182 AC: 1047 AN: 5756

European-Non Finnish (NFE) AF: 0.183 AC: 202618 AN: 1104988

Other (OTH) AF: 0.217 AC: 13056 AN: 60088

GnomAD4 genome AF: 0.270 AC: 41031 AN: 152110 Hom.: 5980 Cov.: 32 AF XY: 0.276 AC XY: 20548 AN XY: 74344

African (AFR) AF: 0.366 AC: 15172 AN: 41460

American (AMR) AF: 0.330 AC: 5046 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3470

East Asian (EAS) AF: 0.290 AC: 1502 AN: 5178

South Asian (SAS) AF: 0.402 AC: 1938 AN: 4818

European-Finnish (FIN) AF: 0.297 AC: 3136 AN: 10574

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 13016 AN: 67990

Other (OTH) AF: 0.242 AC: 512 AN: 2114

Alfa AF: 0.212 Hom.: 7630

Bravo AF: 0.272

Asia WGS AF: 0.359 AC: 1245 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Gillespie syndrome (1)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 15/16 (1)
-	-	1	Spinocerebellar ataxia type 29 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.61
PhyloP100		-1.5
PromoterAI		0.025	Neutral
Mutation Taster		=79/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2306877; hg19: chr3-4716811; COSMIC: COSV56983696; COSMIC: COSV56983696;