3-4814520-C-A

Variant names:

• chr3-4814520-C-A
• NM_001378452.1:c.7659C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001378452.1(ITPR1):​c.7659C>A​(p.Ser2553Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S2553S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 27)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.188

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]

ENSG00000235978 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001378452.1
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.7659C>A	p.Ser2553Arg	missense_variant	Exon 58 of 62	ENST00000649015.2	NP_001365381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.7659C>A	p.Ser2553Arg	missense_variant	Exon 58 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.7635C>A	p.Ser2545Arg	missense_variant	Exon 58 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.7632C>A	p.Ser2544Arg	missense_variant	Exon 58 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.7617C>A	p.Ser2539Arg	missense_variant	Exon 57 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.7614C>A	p.Ser2538Arg	missense_variant	Exon 57 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.7587C>A	p.Ser2529Arg	missense_variant	Exon 55 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.7515C>A	p.Ser2505Arg	missense_variant	Exon 55 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.7470C>A	p.Ser2490Arg	missense_variant	Exon 54 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.5421C>A	p.Ser1807Arg	missense_variant	Exon 38 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.4836C>A	p.Ser1612Arg	missense_variant	Exon 35 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.4599C>A	p.Ser1533Arg	missense_variant	Exon 35 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;N;.;N;.;N;.;.;.;N;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D;D;.;D;.;D;.;.;.;D;.
Sift4G	Uncertain	0.025	D;D;.;D;.;T;.;.;.;D;.
Polyphen		0.99, 1.0	.;.;.;.;.;D;.;D;.;.;.
Vest4		0.79
MutPred		0.39		.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.053);.;.;.;
MVP		0.96
MPC		2.1
ClinPred		0.97	D
GERP RS		-0.25
Varity_R		0.33
gMVP		0.98

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: chr3-4856204;