10-104314436-G-A

Position:

chr10-104314436-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000337478.3(ITPRIP):c.1616C>T(p.Pro539Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,612,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P539T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ITPRIP
ENST00000337478.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

Variant links:

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]

ITPRIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPRIP	NM_001272013.2 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	2/2	ENST00000337478.3	NP_001258942.1	Q8IWB1
ITPRIP	NM_001272012.2 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	2/2		NP_001258941.1	Q8IWB1
ITPRIP	NM_033397.4 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	3/3		NP_203755.1	Q8IWB1
ITPRIP	XM_005270257.3 linkuse as main transcript	c.1631C>T	p.Pro544Leu	missense_variant	2/2		XP_005270314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITPRIP	ENST00000337478.3 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	2/2	1	NM_001272013.2	ENSP00000337178.1	Q8IWB1
ITPRIP	ENST00000278071.6 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	3/3	1		ENSP00000278071.2	Q8IWB1
ITPRIP	ENST00000358187.2 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	2/2	2		ENSP00000350915.2	Q8IWB1
ITPRIP	ENST00000647721.1 linkuse as main transcript	c.1616C>T	p.Pro539Leu	missense_variant	3/3			ENSP00000497746.1	Q8IWB1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249404

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135124

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726300

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000672

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.1616C>T (p.P539L) 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 1616, causing the proline (P) at amino acid position 539 to be replaced by a leucine (L). 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

0.10

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.59

T;.;.;.

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.5

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

N;N;N;.

REVEL

Benign

0.22

Sift

Uncertain

0.0030

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;D;D

Vest4

0.41

MutPred

0.29

Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);

MVP

0.31

MPC

0.66

ClinPred

0.61

GERP RS

5.1

Varity_R

0.047

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over