chr4-142122195-T-C

Variant names:

• chr4-142122195-T-C
• NM_001101669.3:c.2068A>G

Variant summary

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

The NM_001101669.3(INPP4B):​c.2068A>G​(p.Lys690Glu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INPP4B NM_001101669.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24

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=0.1509178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP4B	NM_001101669.3	c.2068A>G	p.Lys690Glu	missense_variant	Exon 21 of 26	ENST00000262992.9	NP_001095139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP4B	ENST00000262992.9	c.2068A>G	p.Lys690Glu	missense_variant	Exon 21 of 26	5	NM_001101669.3	ENSP00000262992.4

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

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2068A>G (p.K690E) alteration is located in exon 22 (coding exon 18) of the INPP4B gene. This alteration results from a A to G substitution at nucleotide position 2068, causing the lysine (K) at amino acid position 690 to be replaced by a glutamic acid (E). 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	0.091
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T;T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.076
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.83	.;T;.;D;D;D;D
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N
REVEL	Benign	0.051
Sift	Uncertain	0.010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;.;.;D
Polyphen		0.089	B;B;B;.;.;.;.
Vest4		0.23
MutPred		0.30		Loss of MoRF binding (P = 0.0743);Loss of MoRF binding (P = 0.0743);Loss of MoRF binding (P = 0.0743);Loss of MoRF binding (P = 0.0743);.;Loss of MoRF binding (P = 0.0743);.;
MVP		0.043
MPC		0.31
ClinPred		0.77	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.43

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: chr4-143043348;