4-142173661-T-G

Variant names:

• chr4-142173661-T-G
• NM_001101669.3:c.1330A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101669.3(INPP4B):​c.1330A>C​(p.Lys444Gln) 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. 13/22 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: 4.18
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19296396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP4B	NM_001101669.3	c.1330A>C	p.Lys444Gln	missense_variant	Exon 16 of 26	ENST00000262992.9	NP_001095139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP4B	ENST00000262992.9	c.1330A>C	p.Lys444Gln	missense_variant	Exon 16 of 26	5	NM_001101669.3	ENSP00000262992.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1330A>C (p.K444Q) alteration is located in exon 17 (coding exon 13) of the INPP4B gene. This alteration results from a A to C substitution at nucleotide position 1330, causing the lysine (K) at amino acid position 444 to be replaced by a glutamine (Q). 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	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.095	T;T;T;T;T;.;T
Eigen	Benign	0.040
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	.;T;.;T;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.;.
PhyloP100		4.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.98	N;N;N;N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.11	T;T;T;T;T;D;T
Sift4G	Benign	0.31	T;T;T;T;.;.;T
Polyphen		0.040	B;B;B;.;.;.;.
Vest4		0.26
MutPred		0.42		Loss of ubiquitination at K444 (P = 0.0017);Loss of ubiquitination at K444 (P = 0.0017);Loss of ubiquitination at K444 (P = 0.0017);Loss of ubiquitination at K444 (P = 0.0017);.;Loss of ubiquitination at K444 (P = 0.0017);.;
MVP		0.17
MPC		0.22
ClinPred		0.64	D
GERP RS		4.5
Varity_R		0.14
gMVP		0.37
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr4-143094814;