Genetic Variant ITPRIP:p.Leu416His (chr10-104314805-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001272013.2(ITPRIP):c.1247T>A(p.Leu416His) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ITPRIP
NM_001272013.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13707703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPRIP	NM_001272013.2 link	c.1247T>A	p.Leu416His	missense_variant	Exon 2 of 2	ENST00000337478.3	NP_001258942.1	Q8IWB1
ITPRIP	NM_001272012.2 link	c.1247T>A	p.Leu416His	missense_variant	Exon 2 of 2		NP_001258941.1	Q8IWB1
ITPRIP	NM_033397.4 link	c.1247T>A	p.Leu416His	missense_variant	Exon 3 of 3		NP_203755.1	Q8IWB1
ITPRIP	XM_005270257.3 link	c.1262T>A	p.Leu421His	missense_variant	Exon 2 of 2		XP_005270314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITPRIP	ENST00000337478.3 link	c.1247T>A	p.Leu416His	missense_variant	Exon 2 of 2	1	NM_001272013.2	ENSP00000337178.1	Q8IWB1
ITPRIP	ENST00000278071.6 link	c.1247T>A	p.Leu416His	missense_variant	Exon 3 of 3	1		ENSP00000278071.2	Q8IWB1
ITPRIP	ENST00000358187.2 link	c.1247T>A	p.Leu416His	missense_variant	Exon 2 of 2	2		ENSP00000350915.2	Q8IWB1
ITPRIP	ENST00000647721.1 link	c.1247T>A	p.Leu416His	missense_variant	Exon 3 of 3			ENSP00000497746.1	Q8IWB1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250244

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135560

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727144

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:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1247T>A (p.L416H) alteration is located in exon 3 (coding exon 1) of the ITPRIP gene. This alteration results from a T to A substitution at nucleotide position 1247, causing the leucine (L) at amino acid position 416 to be replaced by a histidine (H). 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

0.14

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.046

T;T;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.026

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.67

T;.;.;.

M_CAP

Benign

0.0046

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

L;L;L;L

PrimateAI

Uncertain

0.71

PROVEAN

Benign

2.8

N;N;N;.

REVEL

Benign

0.086

Sift

Benign

0.18

T;T;T;.

Sift4G

Uncertain

0.056

T;T;T;.

Polyphen

0.0050

B;B;B;B

Vest4

0.20

MVP

0.11

MPC

0.27

ClinPred

0.34

GERP RS

3.6

Varity_R

0.090

gMVP

0.30

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