10-119823862-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.2209A>G(p.Met737Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INPP5F NM_014937.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

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=0.07897392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5F	NM_014937.4	c.2209A>G	p.Met737Val	missense_variant	19/20	ENST00000650623.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5F	ENST00000650623.2	c.2209A>G	p.Met737Val	missense_variant	19/20		NM_014937.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Oct 22, 2021

The c.2209A>G (p.M737V) alteration is located in exon 19 (coding exon 19) of the INPP5F gene. This alteration results from a A to G substitution at nucleotide position 2209, causing the methionine (M) at amino acid position 737 to be replaced by a valine (V). 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	0.072
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
Dann	Benign	0.90
DEOGEN2	Benign	0.12	T;T;.;.;.;.;.;.;.;T;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.35	N;.;.;.;.;.;.;N;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.31	T;.;.;.;.;.;.;T;.;.;.;.
Sift4G	Benign	1.0	T;.;.;.;.;.;T;T;.;.;T;T
Polyphen		0.0010	B;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.27
MutPred		0.19		Loss of disorder (P = 0.0525);Loss of disorder (P = 0.0525);.;.;.;.;.;.;.;.;.;.;
MVP		0.20
MPC		0.13
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.083
gMVP		0.46

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: rs1851660681; hg19: chr10-121583374;