2-98554278-A-G

Position:

• chr2-98554278-A-G

Variant summary

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

The NM_001134225.2(INPP4A):​c.1355A>G​(p.Gln452Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: INPP4A NM_001134225.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP4A	NM_001134225.2	c.1355A>G	p.Gln452Arg	missense_variant	15/25	ENST00000409851.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP4A	ENST00000409851.8	c.1355A>G	p.Gln452Arg	missense_variant	15/25	1	NM_001134225.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451024 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 16, 2022

The c.1370A>G (p.Q457R) alteration is located in exon 16 (coding exon 14) of the INPP4A gene. This alteration results from a A to G substitution at nucleotide position 1370, causing the glutamine (Q) at amino acid position 457 to be replaced by an arginine (R). 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	0.74
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.084	T;T;T;T;T
Sift4G	Benign	0.85	T;D;D;T;D
Polyphen		0.99	D;D;D;D;D
Vest4		0.76
MutPred		0.31		Gain of MoRF binding (P = 0.0314);.;Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);
MVP		0.48
MPC		1.5
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.38
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1694074165; hg19: chr2-99170741;