10-104314853-G-C

Variant names:

• chr10-104314853-G-C
• NM_001272013.2:c.1199C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001272013.2(ITPRIP):​c.1199C>G​(p.Pro400Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,490 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ITPRIP NM_001272013.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITPRIP	NM_001272013.2	c.1199C>G	p.Pro400Arg	missense_variant	Exon 2 of 2	ENST00000337478.3	NP_001258942.1
ITPRIP	NM_001272012.2	c.1199C>G	p.Pro400Arg	missense_variant	Exon 2 of 2		NP_001258941.1
ITPRIP	NM_033397.4	c.1199C>G	p.Pro400Arg	missense_variant	Exon 3 of 3		NP_203755.1
ITPRIP	XM_005270257.3	c.1214C>G	p.Pro405Arg	missense_variant	Exon 2 of 2		XP_005270314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITPRIP	ENST00000337478.3	c.1199C>G	p.Pro400Arg	missense_variant	Exon 2 of 2	1	NM_001272013.2	ENSP00000337178.1
ITPRIP	ENST00000278071.6	c.1199C>G	p.Pro400Arg	missense_variant	Exon 3 of 3	1		ENSP00000278071.2
ITPRIP	ENST00000358187.2	c.1199C>G	p.Pro400Arg	missense_variant	Exon 2 of 2	2		ENSP00000350915.2
ITPRIP	ENST00000647721.1	c.1199C>G	p.Pro400Arg	missense_variant	Exon 3 of 3			ENSP00000497746.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461490 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1199C>G (p.P400R) alteration is located in exon 3 (coding exon 1) of the ITPRIP gene. This alteration results from a C to G substitution at nucleotide position 1199, causing the proline (P) at amino acid position 400 to be replaced by an arginine (R). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;.;.;.
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.3	M;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.2	D;D;D;.
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;D;D
Vest4		0.85
MutPred		0.65		Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);Gain of MoRF binding (P = 0.0338);
MVP		0.35
MPC		0.83
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.78
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-106074611;