chr3-4814550-G-A

Variant names:

• chr3-4814550-G-A
• rs901854
• NM_001378452.1:c.7689G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001378452.1(ITPR1):​c.7689G>A​(p.Lys2563Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,590,260 control chromosomes in the GnomAD database, including 291,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (26468 hom., cov: 24)
  • Exomes 𝑓: 0.61 (265457 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.44
• Publications: 31 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)

ENSG00000235978 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-4814550-G-A is Benign according to our data. Variant chr3-4814550-G-A is described in ClinVar as Benign. ClinVar VariationId is 129304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.702 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.7689G>A	p.Lys2563Lys	synonymous	Exon 58 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.7644G>A	p.Lys2548Lys	synonymous	Exon 57 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.7545G>A	p.Lys2515Lys	synonymous	Exon 55 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.7689G>A	p.Lys2563Lys	synonymous	Exon 58 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.7665G>A	p.Lys2555Lys	synonymous	Exon 58 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.7662G>A	p.Lys2554Lys	synonymous	Exon 58 of 62	ENSP00000498014.1	A0A3B3IU04

Frequencies

GnomAD3 genomes AF: 0.595 AC: 88686 AN: 148982 Hom.: 26453 Cov.: 24

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.599

GnomAD2 exomes AF: 0.604 AC: 149857 AN: 248248 AF XY: 0.605

Gnomad AFR exome AF: 0.556

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.586

Gnomad EAS exome AF: 0.738

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.608 AC: 876888 AN: 1441170 Hom.: 265457 Cov.: 36 AF XY: 0.609 AC XY: 436309 AN XY: 716730

African (AFR) AF: 0.568 AC: 18559 AN: 32646

American (AMR) AF: 0.534 AC: 23459 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 15383 AN: 25426

East Asian (EAS) AF: 0.722 AC: 27891 AN: 38652

South Asian (SAS) AF: 0.594 AC: 50943 AN: 85706

European-Finnish (FIN) AF: 0.653 AC: 33862 AN: 51844

Middle Eastern (MID) AF: 0.618 AC: 3401 AN: 5506

European-Non Finnish (NFE) AF: 0.608 AC: 667554 AN: 1098430

Other (OTH) AF: 0.607 AC: 35836 AN: 59016

GnomAD4 genome AF: 0.595 AC: 88729 AN: 149090 Hom.: 26468 Cov.: 24 AF XY: 0.594 AC XY: 43117 AN XY: 72560

African (AFR) AF: 0.563 AC: 22746 AN: 40368

American (AMR) AF: 0.549 AC: 8176 AN: 14880

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2043 AN: 3450

East Asian (EAS) AF: 0.722 AC: 3570 AN: 4948

South Asian (SAS) AF: 0.594 AC: 2784 AN: 4686

European-Finnish (FIN) AF: 0.646 AC: 6488 AN: 10046

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.607 AC: 40964 AN: 67468

Other (OTH) AF: 0.592 AC: 1218 AN: 2058

Alfa AF: 0.598 Hom.: 59277

Bravo AF: 0.591

Asia WGS AF: 0.591 AC: 2056 AN: 3478

EpiCase AF: 0.601

EpiControl AF: 0.614

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Gillespie syndrome (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	-0.45
CADD	Benign	9.7
DANN	Benign	0.89
PhyloP100		1.4
PromoterAI		-0.056	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs901854; hg19: chr3-4856234; COSMIC: COSV56999806; COSMIC: COSV56999806;