Genetic Variant INPP5A:p.Gly9Ser (chr10-132538121-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005539.5(INPP5A):c.25G>A(p.Gly9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,241,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

INPP5A
NM_005539.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

Publications

0 publications found

Variant links:

Genes affected

INPP5A (HGNC:6076): (inositol polyphosphate-5-phosphatase A) The protein encoded by this gene is a membrane-associated type I inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. [provided by RefSeq, Jul 2008]

INPP5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011052847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5A	NM_005539.5 link	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 16	ENST00000368594.8	NP_005530.3	Q14642

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPP5A	ENST00000368594.8 link	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 16	1	NM_005539.5	ENSP00000357583.3	Q14642
INPP5A	ENST00000368593.7 link	c.25G>A	p.Gly9Ser	missense_variant	Exon 1 of 13	1		ENSP00000357582.3	Q5T1B5
INPP5A	ENST00000423490.5 link	c.-18G>A		upstream_gene_variant		5		ENSP00000390936.1	Q5T1B3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

151470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000829

AC:

AN:

12066

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

112

AN:

1090110

Hom.:

Cov.:

AF XY:

0.0000984

AC XY:

AN XY:

518464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22884

American (AMR)

AF:

0.00

AC:

AN:

9660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14900

East Asian (EAS)

AF:

0.00

AC:

AN:

26208

South Asian (SAS)

AF:

0.00

AC:

AN:

25094

European-Finnish (FIN)

AF:

0.0000447

AC:

AN:

22366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3402

European-Non Finnish (NFE)

AF:

0.000116

AC:

107

AN:

921896

Other (OTH)

AF:

0.0000915

AC:

AN:

43700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000145

AC:

AN:

151470

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

73954

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67704

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000261

ExAC

AF:

0.0000483

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.25G>A (p.G9S) alteration is located in exon 1 (coding exon 1) of the INPP5A gene. This alteration results from a G to A substitution at nucleotide position 25, causing the glycine (G) at amino acid position 9 to be replaced by a serine (S). 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

0.31

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.089

T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.

PhyloP100

1.3

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.22

N;N

REVEL

Benign

0.098

Sift

Benign

0.63

T;T

Sift4G

Benign

0.78

T;T

Polyphen

0.72

P;P

Vest4

0.18

MutPred

0.33

Gain of glycosylation at G9 (P = 0.0037);Gain of glycosylation at G9 (P = 0.0037);

MVP

0.23

MPC

1.4

ClinPred

0.059

GERP RS

0.089

PromoterAI

0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.046

gMVP

0.40

Mutation Taster

=76/24

polymorphism

(source)

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

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10-132538121-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over