NM_001378452.1:c.6349G>A

Variant names:

• chr3-4779607-G-A
• rs373973399
• NM_001378452.1:c.6349G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_001378452.1(ITPR1):​c.6349G>A​(p.Ala2117Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2117S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.91

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.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPR1	NM_001378452.1	c.6349G>A	p.Ala2117Thr	missense_variant	Exon 49 of 62	ENST00000649015.2	NP_001365381.1
ITPR1	NM_001168272.2	c.6304G>A	p.Ala2102Thr	missense_variant	Exon 48 of 61		NP_001161744.1
ITPR1	NM_001099952.4	c.6205G>A	p.Ala2069Thr	missense_variant	Exon 46 of 59		NP_001093422.2
ITPR1	NM_002222.7	c.6160G>A	p.Ala2054Thr	missense_variant	Exon 45 of 58		NP_002213.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPR1	ENST00000649015.2	c.6349G>A	p.Ala2117Thr	missense_variant	Exon 49 of 62		NM_001378452.1	ENSP00000497605.1
ITPR1	ENST00000354582.12	c.6325G>A	p.Ala2109Thr	missense_variant	Exon 49 of 62	5		ENSP00000346595.8
ITPR1	ENST00000648266.1	c.6322G>A	p.Ala2108Thr	missense_variant	Exon 49 of 62			ENSP00000498014.1
ITPR1	ENST00000650294.1	c.6307G>A	p.Ala2103Thr	missense_variant	Exon 48 of 61			ENSP00000498056.1
ITPR1	ENST00000443694.5	c.6304G>A	p.Ala2102Thr	missense_variant	Exon 48 of 61	1		ENSP00000401671.2
ITPR1	ENST00000648309.1	c.6277G>A	p.Ala2093Thr	missense_variant	Exon 46 of 59			ENSP00000497026.1
ITPR1	ENST00000357086.10	c.6205G>A	p.Ala2069Thr	missense_variant	Exon 46 of 59	1		ENSP00000349597.4
ITPR1	ENST00000456211.8	c.6160G>A	p.Ala2054Thr	missense_variant	Exon 45 of 58	1		ENSP00000397885.2
ITPR1	ENST00000648038.1	c.4111G>A	p.Ala1371Thr	missense_variant	Exon 29 of 42			ENSP00000497872.1
ITPR1	ENST00000648431.1	c.3649G>A	p.Ala1217Thr	missense_variant	Exon 27 of 39			ENSP00000498149.1
ITPR1	ENST00000648212.1	c.3256G>A	p.Ala1086Thr	missense_variant	Exon 25 of 39			ENSP00000498022.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31

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 AF: 0.00000616 AC: 9 AN: 1459922 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74302

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

Alfa AF: 0.0000205 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	D;D;.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0030	D;D;.;D;.;.;.;.;D;.
Sift4G	Uncertain	0.0060	D;D;.;D;.;.;.;.;D;.
Polyphen		0.99	.;.;.;.;.;.;D;.;.;.
Vest4		0.93
MVP		0.78
MPC		1.4
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.69
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373973399; hg19: chr3-4821291; COSMIC: COSV56967721; COSMIC: COSV56967721;