10-119726276-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014937.4(INPP5F):c.14A>G(p.Gln5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000742 in 1,334,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: INPP5F NM_014937.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23745304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5F	NM_014937.4	c.14A>G	p.Gln5Arg	missense_variant	1/20	ENST00000650623.2
INPP5F	NM_001243195.2	c.14A>G	p.Gln5Arg	missense_variant	1/5
INPP5F	XM_006717720.5	c.14A>G	p.Gln5Arg	missense_variant	1/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5F	ENST00000650623.2	c.14A>G	p.Gln5Arg	missense_variant	1/20		NM_014937.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000742 AC: 99 AN: 1334314 Hom.: 0 Cov.: 30 AF XY: 0.0000680 AC XY: 45 AN XY: 661602

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: 0.0000933

Gnomad4 OTH exome AF: 0.0000185

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Apr 26, 2023

The c.14A>G (p.Q5R) alteration is located in exon 1 (coding exon 1) of the INPP5F gene. This alteration results from a A to G substitution at nucleotide position 14, causing the glutamine (Q) at amino acid position 5 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	0.62
BayesDel_addAF	Benign	-0.0052	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Benign	0.95
DEOGEN2	Benign	0.16	T;.;T;.;.
Eigen	Benign	0.076
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.90	L;.;L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.81	N;.;.;.;.
REVEL	Benign	0.058
Sift	Benign	0.33	T;.;.;.;.
Sift4G	Benign	0.43	T;.;.;.;.
Polyphen		0.98	D;.;D;B;.
Vest4		0.20
MutPred		0.30		Loss of methylation at K7 (P = 0.0599);Loss of methylation at K7 (P = 0.0599);Loss of methylation at K7 (P = 0.0599);Loss of methylation at K7 (P = 0.0599);Loss of methylation at K7 (P = 0.0599);
MVP		0.29
MPC		0.59
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.26
gMVP		0.57

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: rs1028755194; hg19: chr10-121485788;