10-119806439-G-A

Variant summary

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

The NM_014937.4(INPP5F):c.1399G>A(p.Val467Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,457,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: INPP5F NM_014937.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.84

Genes affected

INPP5F (HGNC:17054): (inositol polyphosphate-5-phosphatase F) The protein encoded by this gene is an inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase and contains a Sac domain. The activity of this protein is specific for phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

(HGNC:):

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
INPP5F	NM_014937.4	c.1399G>A	p.Val467Met	missense_variant	12/20	ENST00000650623.2
LOC105378513	XR_946359.3	n.465-1742C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5F	ENST00000650623.2	c.1399G>A	p.Val467Met	missense_variant	12/20		NM_014937.4	P1
	ENST00000636592.1	n.744+8049C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457656 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000649 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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 15, 2021

The c.1399G>A (p.V467M) alteration is located in exon 12 (coding exon 12) of the INPP5F gene. This alteration results from a G to A substitution at nucleotide position 1399, causing the valine (V) at amino acid position 467 to be replaced by a methionine (M). 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	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;.;D;.;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Pathogenic	3.7	H;.;H;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.3	N;.;.;.;.;.;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;.;.;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.
Vest4		0.85
MutPred		0.37		Gain of MoRF binding (P = 0.1095);Gain of MoRF binding (P = 0.1095);Gain of MoRF binding (P = 0.1095);.;.;.;.;
MVP		0.45
MPC		0.59
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.31
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs202230159; hg19: chr10-121565951;