NM_001378452.1:c.5867C>A

Variant names:

• chr3-4768652-C-A
• rs769041115
• NM_001378452.1:c.5867C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001378452.1(ITPR1):​c.5867C>A​(p.Ala1956Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ITPR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 44 curated pathogenic missense variants (we use a threshold of 10). The gene has 31 curated benign missense variants. Gene score misZ: 5.5951 (above the threshold of 3.09). Trascript score misZ: 6.2026 (above the threshold of 3.09). GenCC associations: The gene is linked to spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15092587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.5867C>A	p.Ala1956Asp	missense_variant	Exon 46 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.5822C>A	p.Ala1941Asp	missense_variant	Exon 45 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.5723C>A	p.Ala1908Asp	missense_variant	Exon 43 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.5678C>A	p.Ala1893Asp	missense_variant	Exon 42 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.5867C>A	p.Ala1956Asp	missense_variant	Exon 46 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.5843C>A	p.Ala1948Asp	missense_variant	Exon 46 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.5840C>A	p.Ala1947Asp	missense_variant	Exon 46 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.5825C>A	p.Ala1942Asp	missense_variant	Exon 45 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.5822C>A	p.Ala1941Asp	missense_variant	Exon 45 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.5795C>A	p.Ala1932Asp	missense_variant	Exon 43 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.5723C>A	p.Ala1908Asp	missense_variant	Exon 43 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.5678C>A	p.Ala1893Asp	missense_variant	Exon 42 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.3629C>A	p.Ala1210Asp	missense_variant	Exon 26 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3167C>A	p.Ala1056Asp	missense_variant	Exon 24 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.2774C>A	p.Ala925Asp	missense_variant	Exon 22 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.55	.;.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.96	N;N;.;N;.;.;.;.;N;.
REVEL	Uncertain	0.37
Sift	Benign	0.42	T;T;.;T;.;.;.;.;T;.
Sift4G	Benign	0.67	T;T;.;T;.;.;.;.;T;.
Polyphen		0.0	.;.;.;.;.;.;B;.;.;.
Vest4		0.38
MutPred		0.20		.;.;.;.;.;.;Gain of phosphorylation at T1954 (P = 0.0998);.;.;.;
MVP		0.44
MPC		0.22
ClinPred		0.27	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769041115; hg19: chr3-4810336;