10-104315297-G-T

Position:

• chr10-104315297-G-T

Variant summary

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

The NM_001272013.2(ITPRIP):​c.755C>A​(p.Thr252Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,441,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ITPRIP NM_001272013.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00400

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=0.04711598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPRIP	NM_001272013.2	c.755C>A	p.Thr252Lys	missense_variant	2/2	ENST00000337478.3	NP_001258942.1
ITPRIP	NM_001272012.2	c.755C>A	p.Thr252Lys	missense_variant	2/2		NP_001258941.1
ITPRIP	NM_033397.4	c.755C>A	p.Thr252Lys	missense_variant	3/3		NP_203755.1
ITPRIP	XM_005270257.3	c.770C>A	p.Thr257Lys	missense_variant	2/2		XP_005270314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITPRIP	ENST00000337478.3	c.755C>A	p.Thr252Lys	missense_variant	2/2	1	NM_001272013.2	ENSP00000337178.1
ITPRIP	ENST00000278071.6	c.755C>A	p.Thr252Lys	missense_variant	3/3	1		ENSP00000278071.2
ITPRIP	ENST00000358187.2	c.755C>A	p.Thr252Lys	missense_variant	2/2	2		ENSP00000350915.2
ITPRIP	ENST00000647721.1	c.755C>A	p.Thr252Lys	missense_variant	3/3			ENSP00000497746.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1441408 Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1 AN XY: 714378

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: 0.00000455

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Apr 01, 2024

The c.755C>A (p.T252K) alteration is located in exon 3 (coding exon 1) of the ITPRIP gene. This alteration results from a C to A substitution at nucleotide position 755, causing the threonine (T) at amino acid position 252 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.87
DANN	Benign	0.71
DEOGEN2	Benign	0.043	T;T;T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.64	T;.;.;.
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.047	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.10	N;N;N;.
REVEL	Benign	0.079
Sift	Benign	0.39	T;T;T;.
Sift4G	Benign	0.86	T;T;T;.
Polyphen		0.029	B;B;B;B
Vest4		0.16
MutPred		0.32		Gain of solvent accessibility (P = 0.0256);Gain of solvent accessibility (P = 0.0256);Gain of solvent accessibility (P = 0.0256);Gain of solvent accessibility (P = 0.0256);
MVP		0.030
MPC		0.25
ClinPred		0.079	T
GERP RS		4.3
Varity_R		0.046
gMVP		0.28

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: rs1413564038; hg19: chr10-106075055;