4-142160380-G-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.1541C>T(p.Ser514Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPP4B NM_001101669.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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=0.19121635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP4B	NM_001101669.3	c.1541C>T	p.Ser514Leu	missense_variant	17/26	ENST00000262992.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP4B	ENST00000262992.9	c.1541C>T	p.Ser514Leu	missense_variant	17/26	5	NM_001101669.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 10, 2022

The c.1541C>T (p.S514L) alteration is located in exon 18 (coding exon 14) of the INPP4B gene. This alteration results from a C to T substitution at nucleotide position 1541, causing the serine (S) at amino acid position 514 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T;T;T;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.15	T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;.;.;T
Polyphen		0.50	P;P;P;.;.;.;.
Vest4		0.78
MutPred		0.24		Gain of catalytic residue at S514 (P = 0.0057);Gain of catalytic residue at S514 (P = 0.0057);Gain of catalytic residue at S514 (P = 0.0057);Gain of catalytic residue at S514 (P = 0.0057);.;Gain of catalytic residue at S514 (P = 0.0057);.;
MVP		0.12
MPC		0.58
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.20
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1579118811; hg19: chr4-143081533; COSMIC: COSV53727859;