2-98539530-T-C

Position:

• chr2-98539530-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001134225.2(INPP4A):​c.673T>C​(p.Phe225Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 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: INPP4A NM_001134225.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

Genes affected

INPP4A (HGNC:6074): (inositol polyphosphate-4-phosphatase type I A) This gene encodes an Mg++ independent enzyme that hydrolyzes the 4-position phosphate from the inositol ring of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate, and inositol 3,4-bisphosphate. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Aug 2008]

INPP4A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INPP4A	NM_001134225.2	c.673T>C	p.Phe225Leu	missense_variant, splice_region_variant	10/25	ENST00000409851.8	NP_001127697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INPP4A	ENST00000409851.8	c.673T>C	p.Phe225Leu	missense_variant, splice_region_variant	10/25	1	NM_001134225.2	ENSP00000386777.4

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.673T>C (p.F225L) alteration is located in exon 10 (coding exon 8) of the INPP4A gene. This alteration results from a T to C substitution at nucleotide position 673, causing the phenylalanine (F) at amino acid position 225 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Benign	0.88
DEOGEN2	Benign	0.32	.;.;T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D;D;.
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	D;D;D;N;D
REVEL	Benign	0.23
Sift	Benign	0.48	T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.82
MutPred		0.45		Gain of catalytic residue at F225 (P = 0.0785);Gain of catalytic residue at F225 (P = 0.0785);Gain of catalytic residue at F225 (P = 0.0785);Gain of catalytic residue at F225 (P = 0.0785);Gain of catalytic residue at F225 (P = 0.0785);
MVP		0.31
MPC		0.99
ClinPred		0.78	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.75

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: chr2-99155993; COSMIC: COSV99302846;