chr6-33658009-T-G

Position:

• chr6-33658009-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_002224.4(ITPR3):​c.360T>G​(p.Ser120Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPR3 NM_002224.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.992

Genes affected

ITPR3 (HGNC:6182): (inositol 1,4,5-trisphosphate receptor type 3) This gene encodes a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. The receptor contains a calcium channel at the C-terminus and the ligand-binding site at the N-terminus. Knockout studies in mice suggest that type 2 and type 3 inositol 1,4,5-trisphosphate receptors play a key role in exocrine secretion underlying energy metabolism and growth. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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), ITPR3. . Gene score misZ 4.5522 (greater than the threshold 3.09). Trascript score misZ 5.2589 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease, demyelinating, type 1J.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPR3	NM_002224.4	c.360T>G	p.Ser120Arg	missense_variant	4/58	ENST00000605930.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPR3	ENST00000605930.3	c.360T>G	p.Ser120Arg	missense_variant	4/58	1	NM_002224.4	P1
ITPR3	ENST00000374316.9	c.360T>G	p.Ser120Arg	missense_variant	5/59	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ITPR3-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2024

The ITPR3 c.360T>G variant is predicted to result in the amino acid substitution p.Ser120Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.93	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.64
Sift	Benign	0.059	T;.
Sift4G	Benign	0.11	T;T
Polyphen		0.83	P;P
Vest4		0.74
MutPred		0.64		Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);
MVP		0.71
MPC		1.4
ClinPred		0.85	D
GERP RS		-8.8
Varity_R		0.22
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1444659269; hg19: chr6-33625786;