rs61757110

chr3-4693723-C-Achr3-4693723-C-Gchr3-4693723-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001378452.1(ITPR1):c.4263C>A(p.His1421Gln) variant causes a missense 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1421H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ITPR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.37755185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.4263C>A	p.His1421Gln	missense_variant	33/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.4218C>A	p.His1406Gln	missense_variant	32/61
ITPR1	NM_001099952.4	c.4236C>A	p.His1412Gln	missense_variant	33/59
ITPR1	NM_002222.7	c.4191C>A	p.His1397Gln	missense_variant	32/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.4263C>A	p.His1421Gln	missense_variant	33/62		NM_001378452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	10
Dann	Benign	0.97
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;.;D;.;.;.;.;D;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0030	D;D;.;D;.;.;.;.;D;.
Polyphen		1.0	.;.;.;.;.;.;D;.;.;.
Vest4		0.79
MutPred		0.37		.;.;.;.;.;.;Loss of catalytic residue at D1423 (P = 0.1755);.;.;.;
MVP		0.84
MPC		1.5
ClinPred		0.99	D
GERP RS		-9.2
Varity_R		0.68
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-4735407;