rs34748547

Variant names:

• chr3-4702916-C-T
• rs34748547
• NM_001378452.1:c.4623C>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.4623C>T​(p.Ser1541Ser) 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:5
• Conservation: PhyloP100: -4.77
• Publications: 6 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: G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• spinocerebellar ataxia type 29

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

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 345738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 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.4623C>T	p.Ser1541Ser	synonymous	Exon 36 of 62	NP_001365381.1	Q14643-1
	ITPR1	NM_001168272.2		c.4578C>T	p.Ser1526Ser	synonymous	Exon 35 of 61	NP_001161744.1	Q14643-2
	ITPR1	NM_001099952.4		c.4596C>T	p.Ser1532Ser	synonymous	Exon 36 of 59	NP_001093422.2	Q14643-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPR1	ENST00000649015.2	MANE Select	c.4623C>T	p.Ser1541Ser	synonymous	Exon 36 of 62	ENSP00000497605.1	Q14643-1
	ITPR1	ENST00000354582.12	TSL:5	c.4596C>T	p.Ser1532Ser	synonymous	Exon 36 of 62	ENSP00000346595.8	A0A3F2YNW8
	ITPR1	ENST00000648266.1		c.4596C>T	p.Ser1532Ser	synonymous	Exon 36 of 62	ENSP00000498014.1	A0A3B3IU04

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

GnomAD2 exomes AF: 0.00398 AC: 992 AN: 249156 AF XY: 0.00318

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 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

African (AFR) AF: 0.0481 AC: 1611 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00143 AC: 123 AN: 86246

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53398

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000226 AC: 251 AN: 1111818

Other (OTH) AF: 0.00335 AC: 202 AN: 60368

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

African (AFR) AF: 0.0464 AC: 1929 AN: 41538

American (AMR) AF: 0.00412 AC: 63 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.00650 Hom.: 16

Bravo AF: 0.0149

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant cerebellar ataxia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.1
DANN	Benign	0.86
PhyloP100		-4.8
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: rs34748547; hg19: chr3-4744600;