rs563347395

Variant names:

• chr3-4627794-C-G
• rs563347395
• NM_001378452.1:c.195C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-4627794-C-G
• chr3-4627794-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.195C>G​(p.Arg65Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000913 in 1,613,640 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (33 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.295
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 3-4627794-C-G is Benign according to our data. Variant chr3-4627794-C-G is described in ClinVar as Benign. ClinVar VariationId is 345544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.295 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000486 (74/152204) while in subpopulation SAS AF = 0.0147 (71/4828). AF 95% confidence interval is 0.012. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 33 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.195C>G	p.Arg65Arg	synonymous	Exon 5 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.195C>G	p.Arg65Arg	synonymous	Exon 5 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.195C>G	p.Arg65Arg	synonymous	Exon 5 of 59	NP_001093422.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.195C>G	p.Arg65Arg	synonymous	Exon 5 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.195C>G	p.Arg65Arg	synonymous	Exon 5 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.195C>G	p.Arg65Arg	synonymous	Exon 5 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00188 AC: 468 AN: 249250 AF XY: 0.00257

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: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000957 AC: 1399 AN: 1461436 Hom.: 33 Cov.: 30 AF XY: 0.00142 AC XY: 1033 AN XY: 727004

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0152 AC: 1313 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111686

Other (OTH) AF: 0.000746 AC: 45 AN: 60358

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74404

African (AFR) AF: 0.0000241 AC: 1 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	ITPR1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.3
DANN	Benign	0.66
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=84/16	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: rs563347395; hg19: chr3-4669478; COSMIC: COSV107310863;