rs34748547

Positions:

• chr3-4702916-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.4623C>T​(p.Ser1541=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,898 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (51 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.77

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 3-4702916-C-T is Benign according to our data. Variant chr3-4702916-C-T is described in ClinVar as [Benign]. Clinvar id is 345738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-4702916-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2042/152266) while in subpopulation AFR AF= 0.0464 (1929/41538). AF 95% confidence interval is 0.0447. There are 53 homozygotes in gnomad4. There are 971 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.4623C>T	p.Ser1541=	synonymous_variant	36/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.4578C>T	p.Ser1526=	synonymous_variant	35/61
ITPR1	NM_001099952.4	c.4596C>T	p.Ser1532=	synonymous_variant	36/59
ITPR1	NM_002222.7	c.4551C>T	p.Ser1517=	synonymous_variant	35/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.4623C>T	p.Ser1541=	synonymous_variant	36/62		NM_001378452.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2039 AN: 152148 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00398 AC: 992 AN: 249156 Hom.: 27 AF XY: 0.00318 AC XY: 430 AN XY: 135180

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00165 AC: 2408 AN: 1461632 Hom.: 51 Cov.: 30 AF XY: 0.00148 AC XY: 1074 AN XY: 727096

Gnomad4 AFR exome AF: 0.0481

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.00335

GnomAD4 genome AF: 0.0134 AC: 2042 AN: 152266 Hom.: 53 Cov.: 32 AF XY: 0.0130 AC XY: 971 AN XY: 74452

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00655 Hom.: 13

Bravo AF: 0.0149

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 09, 2020

- -

Autosomal dominant cerebellar ataxia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.1
DANN	Benign	0.86

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: rs34748547; hg19: chr3-4744600;