10-104314608-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001272013.2(ITPRIP):c.1444C>T(p.Arg482Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: ITPRIP NM_001272013.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

Genes affected

ITPRIP (HGNC:29370): (inositol 1,4,5-trisphosphate receptor interacting protein) This gene encodes a membrane-associated protein that binds the inositol 1,4,5-trisphosphate receptor (ITPR). The encoded protein enhances the sensitivity of ITPR to intracellular calcium signaling. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010545731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPRIP	NM_001272013.2	c.1444C>T	p.Arg482Cys	missense_variant	2/2	ENST00000337478.3
ITPRIP	NM_001272012.2	c.1444C>T	p.Arg482Cys	missense_variant	2/2
ITPRIP	NM_033397.4	c.1444C>T	p.Arg482Cys	missense_variant	3/3
ITPRIP	XM_005270257.3	c.1459C>T	p.Arg487Cys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPRIP	ENST00000337478.3	c.1444C>T	p.Arg482Cys	missense_variant	2/2	1	NM_001272013.2	P1
ITPRIP	ENST00000278071.6	c.1444C>T	p.Arg482Cys	missense_variant	3/3	1		P1
ITPRIP	ENST00000358187.2	c.1444C>T	p.Arg482Cys	missense_variant	2/2	2		P1
ITPRIP	ENST00000647721.1	c.1444C>T	p.Arg482Cys	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251128 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135812

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461814 Hom.: 1 Cov.: 34 AF XY: 0.000118 AC XY: 86 AN XY: 727214

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74504

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1444C>T (p.R482C) alteration is located in exon 3 (coding exon 1) of the ITPRIP gene. This alteration results from a C to T substitution at nucleotide position 1444, causing the arginine (R) at amino acid position 482 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;.;.;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	0.72	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N;N;N;.
REVEL	Benign	0.034
Sift	Benign	0.037	D;D;D;.
Sift4G	Uncertain	0.051	T;T;T;.
Polyphen		0.022	B;B;B;B
Vest4		0.15
MVP		0.32
MPC		0.30
ClinPred		0.029	T
GERP RS		4.2
Varity_R		0.059
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs201488821; hg19: chr10-106074366;