rs61757111

Variant names:

• chr3-4733132-C-T
• rs61757111
• NM_001378452.1:c.5265C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.5265C>T​(p.Asn1755Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,816 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (5 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.344
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 3-4733132-C-T is Benign according to our data. Variant chr3-4733132-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197067.
• BP7: Synonymous conserved (PhyloP=0.344 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (319/152336) while in subpopulation NFE AF = 0.00357 (243/68034). AF 95% confidence interval is 0.0032. There are 2 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.5265C>T	p.Asn1755Asn	synonymous	Exon 43 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.5220C>T	p.Asn1740Asn	synonymous	Exon 42 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.5121C>T	p.Asn1707Asn	synonymous	Exon 40 of 59	NP_001093422.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.5265C>T	p.Asn1755Asn	synonymous	Exon 43 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.5241C>T	p.Asn1747Asn	synonymous	Exon 43 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.5238C>T	p.Asn1746Asn	synonymous	Exon 43 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00192 AC: 478 AN: 248698 AF XY: 0.00189

Gnomad AFR exome AF: 0.000647

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.00498

Gnomad EAS exome AF: 0.000725

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00301 AC: 4400 AN: 1461480 Hom.: 5 Cov.: 31 AF XY: 0.00288 AC XY: 2094 AN XY: 727008

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 131 AN: 26128

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39694

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86204

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00359 AC: 3996 AN: 1111764

Other (OTH) AF: 0.00205 AC: 124 AN: 60368

GnomAD4 genome AF: 0.00209 AC: 319 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74478

African (AFR) AF: 0.00101 AC: 42 AN: 41582

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00194

EpiCase AF: 0.00240

EpiControl AF: 0.00279

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		0.34
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61757111; hg19: chr3-4774816;