chr2-190366869-T-C

Position:

• chr2-190366869-T-C

Variant summary

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

The NM_001128928.2(INPP1):​c.440T>C​(p.Ile147Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: INPP1 NM_001128928.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0610

Genes affected

INPP1 (HGNC:6071): (inositol polyphosphate-1-phosphatase) This gene encodes the enzyme inositol polyphosphate-1-phosphatase, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 1 of the inositol ring from the polyphosphates inositol 1,4-bisphosphate and inositol 1,3,4-trisphophosphate. [provided by RefSeq, Jul 2008]

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=0.033257335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP1	NM_001128928.2	c.440T>C	p.Ile147Thr	missense_variant	5/7	ENST00000392329.7	NP_001122400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP1	ENST00000392329.7	c.440T>C	p.Ile147Thr	missense_variant	5/7	5	NM_001128928.2	ENSP00000376142.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Mar 25, 2024

The c.440T>C (p.I147T) alteration is located in exon 5 (coding exon 3) of the INPP1 gene. This alteration results from a T to C substitution at nucleotide position 440, causing the isoleucine (I) at amino acid position 147 to be replaced by a threonine (T). 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	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.0
DANN	Benign	0.53
DEOGEN2	Benign	0.026	T;T;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.54	T;.;T;T;T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.033	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N;N;.;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.0	N;N;N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.59	T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T
Polyphen		0.0	B;B;.;.;.;.
Vest4		0.080
MutPred		0.30		Loss of stability (P = 0.029);Loss of stability (P = 0.029);Loss of stability (P = 0.029);Loss of stability (P = 0.029);Loss of stability (P = 0.029);Loss of stability (P = 0.029);
MVP		0.067
MPC		0.32
ClinPred		0.018	T
GERP RS		-3.1
Varity_R		0.022
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr2-191231595;