chr4-142124760-T-A

Position:

• chr4-142124760-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101669.3(INPP4B):​c.1721A>T​(p.Glu574Val) variant causes a missense, splice region 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. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPP4B NM_001101669.3 missense, splice_region
• Scores: Splicing: ADA: 0.004006
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

Genes affected

INPP4B (HGNC:6075): (inositol polyphosphate-4-phosphatase type II B) INPP4B encodes the inositol polyphosphate 4-phosphatase type II, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate. There is limited data to suggest that the human type II enzyme is subject to alternative splicing, as has been established for the type I enzyme. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.13072145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP4B	NM_001101669.3	c.1721A>T	p.Glu574Val	missense_variant, splice_region_variant	19/26	ENST00000262992.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP4B	ENST00000262992.9	c.1721A>T	p.Glu574Val	missense_variant, splice_region_variant	19/26	5	NM_001101669.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 14, 2022

The c.1721A>T (p.E574V) alteration is located in exon 20 (coding exon 16) of the INPP4B gene. This alteration results from a A to T substitution at nucleotide position 1721, causing the glutamic acid (E) at amino acid position 574 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T;T;T;T;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L;L;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;.;.;T
Polyphen		0.020	B;B;B;.;.;.;.
Vest4		0.37
MutPred		0.36		Loss of solvent accessibility (P = 0.0052);Loss of solvent accessibility (P = 0.0052);Loss of solvent accessibility (P = 0.0052);Loss of solvent accessibility (P = 0.0052);.;Loss of solvent accessibility (P = 0.0052);.;
MVP		0.14
MPC		0.23
ClinPred		0.39	T
GERP RS		4.6
Varity_R		0.086
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.090		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: chr4-143045913;