3-4516359-A-G

Position:

• chr3-4516359-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001378452.1(ITPR1):​c.-16-117A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00844 in 556,064 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (19 hom.)
• Consequence: ITPR1 NM_001378452.1 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.548

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 3-4516359-A-G is Benign according to our data. Variant chr3-4516359-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1219513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00716 (1090/152326) while in subpopulation NFE AF= 0.0103 (701/68036). AF 95% confidence interval is 0.00967. There are 6 homozygotes in gnomad4. There are 530 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.-16-117A>G		intron_variant		ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.-16-117A>G		intron_variant			NP_001161744.1
ITPR1	NM_001099952.4	c.-16-117A>G		intron_variant			NP_001093422.2
ITPR1	NM_002222.7	c.-16-117A>G		intron_variant			NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.-16-117A>G		intron_variant			NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.-16-117A>G		intron_variant		5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.-16-117A>G		intron_variant				ENSP00000498014.1
ITPR1	ENST00000650294.1	c.-16-117A>G		intron_variant				ENSP00000498056.1
ITPR1	ENST00000443694.5	c.-16-117A>G		intron_variant		1		ENSP00000401671.2
ITPR1	ENST00000357086.10	c.-16-117A>G		intron_variant		1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.-16-117A>G		intron_variant		1		ENSP00000397885.2

Frequencies

GnomAD3 genomes AF: 0.00717 AC: 1092 AN: 152208 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00692

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00892 AC: 3603 AN: 403738 Hom.: 19 AF XY: 0.00907 AC XY: 1925 AN XY: 212332

Gnomad4 AFR exome AF: 0.00273

Gnomad4 AMR exome AF: 0.00634

Gnomad4 ASJ exome AF: 0.00874

Gnomad4 EAS exome AF: 0.00258

Gnomad4 SAS exome AF: 0.0100

Gnomad4 FIN exome AF: 0.00434

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00937

GnomAD4 genome AF: 0.00716 AC: 1090 AN: 152326 Hom.: 6 Cov.: 33 AF XY: 0.00712 AC XY: 530 AN XY: 74488

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00674

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00990 Hom.: 0

Bravo AF: 0.00730

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.79

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: rs73003291; hg19: chr3-4558043;