3-4627794-C-T

Variant names:

• chr3-4627794-C-T
• rs563347395
• NM_001378452.1:c.195C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001378452.1(ITPR1):​c.195C>T​(p.Arg65Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R65R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.295
• Publications: 0 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)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP7: Synonymous conserved (PhyloP=0.295 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 3 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.195C>T	p.Arg65Arg	synonymous_variant	Exon 5 of 58	1		ENSP00000397885.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.60
PhyloP100		0.29

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: rs563347395; hg19: chr3-4669478;