3-4658161-G-T

Position:

• chr3-4658161-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001378452.1(ITPR1):​c.1034G>T​(p.Arg345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,976 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R345Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPR1 NM_001378452.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ITPR1. . Gene score misZ 5.5951 (greater than the threshold 3.09). Trascript score misZ 6.2026 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 15/16, aniridia-cerebellar ataxia-intellectual disability syndrome, spinocerebellar ataxia type 29.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR1	NM_001378452.1	c.1034G>T	p.Arg345Leu	missense_variant	13/62	ENST00000649015.2
ITPR1	NM_001168272.2	c.989G>T	p.Arg330Leu	missense_variant	12/61
ITPR1	NM_001099952.4	c.1034G>T	p.Arg345Leu	missense_variant	13/59
ITPR1	NM_002222.7	c.989G>T	p.Arg330Leu	missense_variant	12/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR1	ENST00000649015.2	c.1034G>T	p.Arg345Leu	missense_variant	13/62		NM_001378452.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248808 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134984

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460976 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726758

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.9	D;D;D;D;.;.;.;.;D
REVEL	Uncertain	0.50
Sift	Benign	0.26	T;T;T;T;.;.;.;.;T
Sift4G	Benign	0.092	T;T;.;T;.;.;.;.;T
Polyphen		0.074	.;.;.;.;.;.;B;.;.
Vest4		0.57
MutPred		0.69		Loss of MoRF binding (P = 0.0349);.;Loss of MoRF binding (P = 0.0349);.;Loss of MoRF binding (P = 0.0349);.;Loss of MoRF binding (P = 0.0349);.;.;
MVP		0.84
MPC		0.97
ClinPred		0.76	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.65

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: rs201804963; hg19: chr3-4699845;