chr3-4775379-G-A

Variant names:

• chr3-4775379-G-A
• rs139528715
• NM_001378452.1:c.6117G>A

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.6117G>A​(p.Ala2039Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,613,670 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.10

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=-0.86).
• BP6: Variant 3-4775379-G-A is Benign according to our data. Variant chr3-4775379-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00265 (403/152288) while in subpopulation AFR AF= 0.00907 (377/41560). AF 95% confidence interval is 0.00832. There are 5 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6117G>A	p.Ala2039Ala	synonymous_variant	Exon 47 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6072G>A	p.Ala2024Ala	synonymous_variant	Exon 46 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5973G>A	p.Ala1991Ala	synonymous_variant	Exon 44 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5928G>A	p.Ala1976Ala	synonymous_variant	Exon 43 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6117G>A	p.Ala2039Ala	synonymous_variant	Exon 47 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.6093G>A	p.Ala2031Ala	synonymous_variant	Exon 47 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.6090G>A	p.Ala2030Ala	synonymous_variant	Exon 47 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.6075G>A	p.Ala2025Ala	synonymous_variant	Exon 46 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6072G>A	p.Ala2024Ala	synonymous_variant	Exon 46 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6045G>A	p.Ala2015Ala	synonymous_variant	Exon 44 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5973G>A	p.Ala1991Ala	synonymous_variant	Exon 44 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5928G>A	p.Ala1976Ala	synonymous_variant	Exon 43 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3879G>A	p.Ala1293Ala	synonymous_variant	Exon 27 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3417G>A	p.Ala1139Ala	synonymous_variant	Exon 25 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3024G>A	p.Ala1008Ala	synonymous_variant	Exon 23 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152170 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00907

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000626 AC: 156 AN: 249232 Hom.: 1 AF XY: 0.000533 AC XY: 72 AN XY: 135204

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000298 AC: 436 AN: 1461382 Hom.: 3 Cov.: 32 AF XY: 0.000260 AC XY: 189 AN XY: 727028

Gnomad4 AFR exome AF: 0.00833

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152288 Hom.: 5 Cov.: 33 AF XY: 0.00269 AC XY: 200 AN XY: 74456

Gnomad4 AFR AF: 0.00907

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.00298

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 03, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 14, 2016

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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	-0.86
CADD	Benign	0.93
DANN	Benign	0.32

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: rs139528715; hg19: chr3-4817063;