3-4710336-C-T

Variant names:

• chr3-4710336-C-T
• rs373127487
• NM_001378452.1:c.4854C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378452.1(ITPR1):​c.4854C>T​(p.Ser1618Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,560,426 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 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.35
• Publications: 1 publications found

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]

ITPR1 Gene-Disease associations (from GenCC):

• aniridia-cerebellar ataxia-intellectual disability syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• spinocerebellar ataxia type 29

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• spinocerebellar ataxia type 15/16

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

LOC124906210 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-4710336-C-T is Benign according to our data. Variant chr3-4710336-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 345741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000355 (54/152274) while in subpopulation AMR AF = 0.000653 (10/15304). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378452.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	NM_001378452.1	MANE Select	c.4854C>T	p.Ser1618Ser	synonymous	Exon 38 of 62	NP_001365381.1
	ITPR1	NM_001168272.2		c.4809C>T	p.Ser1603Ser	synonymous	Exon 37 of 61	NP_001161744.1
	ITPR1	NM_001099952.4		c.4827C>T	p.Ser1609Ser	synonymous	Exon 38 of 59	NP_001093422.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.4854C>T	p.Ser1618Ser	synonymous	Exon 38 of 62	ENSP00000497605.1
	ITPR1	ENST00000354582.12	TSL:5	c.4827C>T	p.Ser1609Ser	synonymous	Exon 38 of 62	ENSP00000346595.8
	ITPR1	ENST00000648266.1		c.4827C>T	p.Ser1609Ser	synonymous	Exon 38 of 62	ENSP00000498014.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000470 AC: 87 AN: 185276 AF XY: 0.000497

Gnomad AFR exome AF: 0.000277

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000511

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000429 AC: 604 AN: 1408152 Hom.: 2 Cov.: 30 AF XY: 0.000442 AC XY: 307 AN XY: 694762

African (AFR) AF: 0.000402 AC: 13 AN: 32354

American (AMR) AF: 0.00108 AC: 41 AN: 38114

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25162

East Asian (EAS) AF: 0.0000805 AC: 3 AN: 37284

South Asian (SAS) AF: 0.0000876 AC: 7 AN: 79946

European-Finnish (FIN) AF: 0.0000395 AC: 2 AN: 50668

Middle Eastern (MID) AF: 0.0109 AC: 58 AN: 5334

European-Non Finnish (NFE) AF: 0.000409 AC: 442 AN: 1081064

Other (OTH) AF: 0.000635 AC: 37 AN: 58226

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74452

African (AFR) AF: 0.000144 AC: 6 AN: 41544

American (AMR) AF: 0.000653 AC: 10 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	ITPR1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.66
PhyloP100		-4.4
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs373127487; hg19: chr3-4752020;