NM_001101669.3:c.2205A>C

Variant names:

• chr4-142112613-T-G
• NM_001101669.3:c.2205A>C

Variant summary

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

The NM_001101669.3(INPP4B):​c.2205A>C​(p.Glu735Asp) 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. 14/21 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: INPP4B NM_001101669.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 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=0.061365873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP4B	NM_001101669.3	c.2205A>C	p.Glu735Asp	missense_variant	Exon 22 of 26	ENST00000262992.9	NP_001095139.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP4B	ENST00000262992.9	c.2205A>C	p.Glu735Asp	missense_variant	Exon 22 of 26	5	NM_001101669.3	ENSP00000262992.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2205A>C (p.E735D) alteration is located in exon 23 (coding exon 19) of the INPP4B gene. This alteration results from a A to C substitution at nucleotide position 2205, causing the glutamic acid (E) at amino acid position 735 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;T;T;T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.67	.;T;.;T;T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.061	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.55	N;N;N;N;N;N;N
REVEL	Benign	0.052
Sift	Benign	0.36	T;T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;.;.;T
Polyphen		0.033	B;B;B;.;.;.;.
Vest4		0.29
MutPred		0.26		Loss of methylation at K734 (P = 0.085);Loss of methylation at K734 (P = 0.085);Loss of methylation at K734 (P = 0.085);Loss of methylation at K734 (P = 0.085);.;Loss of methylation at K734 (P = 0.085);.;
MVP		0.082
MPC		0.19
ClinPred		0.32	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.37

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: chr4-143033766;