rs562572079

Positions:

• chr3-4675202-G-A
• chr3-4675202-G-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.2733G>A​(p.Ala911Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,624 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (2 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58

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=-0.81).
• BP6: Variant 3-4675202-G-A is Benign according to our data. Variant chr3-4675202-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 447582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000985 (15/152304) while in subpopulation SAS AF= 0.00104 (5/4820). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.2733G>A	p.Ala911Ala	synonymous_variant	23/62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.2688G>A	p.Ala896Ala	synonymous_variant	22/61		NP_001161744.1
ITPR1	NM_001099952.4	c.2733G>A	p.Ala911Ala	synonymous_variant	23/59		NP_001093422.2
ITPR1	NM_002222.7	c.2688G>A	p.Ala896Ala	synonymous_variant	22/58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.2733G>A	p.Ala911Ala	synonymous_variant	23/62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.2733G>A	p.Ala911Ala	synonymous_variant	23/62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.2733G>A	p.Ala911Ala	synonymous_variant	23/62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.2688G>A	p.Ala896Ala	synonymous_variant	22/61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.2688G>A	p.Ala896Ala	synonymous_variant	22/61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.2688G>A	p.Ala896Ala	synonymous_variant	20/59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.2733G>A	p.Ala911Ala	synonymous_variant	23/59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.2688G>A	p.Ala896Ala	synonymous_variant	22/58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.570G>A	p.Ala190Ala	synonymous_variant	4/42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.60G>A	p.Ala20Ala	synonymous_variant	1/39			ENSP00000498149.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000928 AC: 23 AN: 247720 Hom.: 0 AF XY: 0.000127 AC XY: 17 AN XY: 134378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.000563

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000644 AC: 94 AN: 1460320 Hom.: 2 Cov.: 30 AF XY: 0.0000798 AC XY: 58 AN XY: 726388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000769

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 15, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.4
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs562572079; hg19: chr3-4716886; COSMIC: COSV56996061; COSMIC: COSV56996061;