chr10-104315282-C-T

Position:

chr10-104315282-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000337478.3(ITPRIP):c.770G>A(p.Cys257Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,600,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ITPRIP
ENST00000337478.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.50

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITPRIP	NM_001272013.2 linkuse as main transcript	c.770G>A	p.Cys257Tyr	missense_variant	2/2	ENST00000337478.3	NP_001258942.1	Q8IWB1
ITPRIP	NM_001272012.2 linkuse as main transcript	c.770G>A	p.Cys257Tyr	missense_variant	2/2		NP_001258941.1	Q8IWB1
ITPRIP	NM_033397.4 linkuse as main transcript	c.770G>A	p.Cys257Tyr	missense_variant	3/3		NP_203755.1	Q8IWB1
ITPRIP	XM_005270257.3 linkuse as main transcript	c.785G>A	p.Cys262Tyr	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.770G>A	p.Cys257Tyr	missense_variant	2/2	1	NM_001272013.2	ENSP00000337178.1	Q8IWB1
ITPRIP	ENST00000278071.6 linkuse as main transcript	c.770G>A	p.Cys257Tyr	missense_variant	3/3	1		ENSP00000278071.2	Q8IWB1
ITPRIP	ENST00000358187.2 linkuse as main transcript	c.770G>A	p.Cys257Tyr	missense_variant	2/2	2		ENSP00000350915.2	Q8IWB1
ITPRIP	ENST00000647721.1 linkuse as main transcript	c.770G>A	p.Cys257Tyr	missense_variant	3/3			ENSP00000497746.1	Q8IWB1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000125

AC:

AN:

239148

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129030

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000280

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000552

AC:

AN:

1448262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718860

show subpopulations

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:

0.0000189

Gnomad4 NFE exome

AF:

0.00000634

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

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

Feb 21, 2024

The c.770G>A (p.C257Y) alteration is located in exon 3 (coding exon 1) of the ITPRIP gene. This alteration results from a G to A substitution at nucleotide position 770, causing the cysteine (C) at amino acid position 257 to be replaced by a tyrosine (Y). 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

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

T;.;.;.

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.6

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-8.4

D;D;D;.

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;D;D

Vest4

0.93

MutPred

0.88

Gain of catalytic residue at I256 (P = 0.045);Gain of catalytic residue at I256 (P = 0.045);Gain of catalytic residue at I256 (P = 0.045);Gain of catalytic residue at I256 (P = 0.045);

MVP

0.41

MPC

1.1

ClinPred

0.99

GERP RS

5.3

Varity_R

0.92

gMVP

0.87

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