Genetic Variant INPP5A:p.Thr10Ile (chr10-132538125-C-T) – 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.29C>T(p.Thr10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 1,252,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000073 ( 0 hom. )

Consequence

INPP5A
NM_005539.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0290

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=0.013605118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5A	NM_005539.5 link	c.29C>T	p.Thr10Ile	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.29C>T	p.Thr10Ile	missense_variant	Exon 1 of 16	1	NM_005539.5	ENSP00000357583.3	Q14642
INPP5A	ENST00000368593.7 link	c.29C>T	p.Thr10Ile	missense_variant	Exon 1 of 13	1		ENSP00000357582.3	Q5T1B5
INPP5A	ENST00000423490.5 link	c.-14C>T		upstream_gene_variant		5		ENSP00000390936.1	Q5T1B3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000600

AC:

AN:

16658

AF XY:

0.0000981

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000727

AC:

AN:

1100512

Hom.:

Cov.:

AF XY:

0.00000762

AC XY:

AN XY:

524954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23136

American (AMR)

AF:

0.00

AC:

AN:

10746

Ashkenazi Jewish (ASJ)

AF:

0.0000653

AC:

AN:

15320

East Asian (EAS)

AF:

0.00

AC:

AN:

26404

South Asian (SAS)

AF:

0.0000726

AC:

AN:

27532

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3568

European-Non Finnish (NFE)

AF:

0.00000539

AC:

AN:

926816

Other (OTH)

AF:

0.00

AC:

AN:

44156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74006

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41362

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67746

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000233

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.29C>T (p.T10I) alteration is located in exon 1 (coding exon 1) of the INPP5A gene. This alteration results from a C to T substitution at nucleotide position 29, causing the threonine (T) at amino acid position 10 to be replaced by an isoleucine (I). 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

0.28

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.51

N;.

PhyloP100

-0.029

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.52

N;N

REVEL

Benign

0.12

Sift

Benign

0.32

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.98

D;D

Vest4

0.26

MutPred

0.37

Loss of catalytic residue at T10 (P = 0.0382);Loss of catalytic residue at T10 (P = 0.0382);

MVP

0.29

MPC

1.1

ClinPred

0.13

GERP RS

2.1

PromoterAI

-0.0020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.068

gMVP

0.37

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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10-132538125-C-T

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