rs371661663

Variant names:

• chr3-4766676-T-C
• rs371661663
• NM_001378452.1:c.5691T>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_001378452.1(ITPR1):​c.5691T>C​(p.Asp1897Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000831 in 1,612,470 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.63

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-4766676-T-C is Benign according to our data. Variant chr3-4766676-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447593.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000087 (127/1460194) while in subpopulation NFE AF= 0.000103 (114/1111246). AF 95% confidence interval is 0.0000868. There are 0 homozygotes in gnomad4_exome. There are 64 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5691T>C	p.Asp1897Asp	synonymous_variant	Exon 45 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5646T>C	p.Asp1882Asp	synonymous_variant	Exon 44 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5547T>C	p.Asp1849Asp	synonymous_variant	Exon 42 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5502T>C	p.Asp1834Asp	synonymous_variant	Exon 41 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5691T>C	p.Asp1897Asp	synonymous_variant	Exon 45 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5667T>C	p.Asp1889Asp	synonymous_variant	Exon 45 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5664T>C	p.Asp1888Asp	synonymous_variant	Exon 45 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5649T>C	p.Asp1883Asp	synonymous_variant	Exon 44 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5646T>C	p.Asp1882Asp	synonymous_variant	Exon 44 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5619T>C	p.Asp1873Asp	synonymous_variant	Exon 42 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5547T>C	p.Asp1849Asp	synonymous_variant	Exon 42 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5502T>C	p.Asp1834Asp	synonymous_variant	Exon 41 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3453T>C	p.Asp1151Asp	synonymous_variant	Exon 25 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.2991T>C	p.Asp997Asp	synonymous_variant	Exon 23 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2598T>C	p.Asp866Asp	synonymous_variant	Exon 21 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000564 AC: 14 AN: 248214 Hom.: 0 AF XY: 0.0000743 AC XY: 10 AN XY: 134638

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000870 AC: 127 AN: 1460194 Hom.: 0 Cov.: 31 AF XY: 0.0000881 AC XY: 64 AN XY: 726378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant cerebellar ataxia Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

May 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.12
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs371661663; hg19: chr3-4808360; COSMIC: COSV56973840; COSMIC: COSV56973840;