Genetic Variant INPP5F:p.Asn997Asp (chr10-119827370-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014937.4(INPP5F):c.2989A>G(p.Asn997Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,613,804 control chromosomes in the GnomAD database, including 87,431 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7209 hom., cov: 32)

Exomes 𝑓: 0.33 ( 80222 hom. )

Consequence

INPP5F
NM_014937.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.14

Publications

46 publications found

Variant links:

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]

INPP5F links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004123211).

BP6

Variant 10-119827370-A-G is Benign according to our data. Variant chr10-119827370-A-G is described in ClinVar as [Benign]. Clinvar id is 1232724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5F	NM_014937.4 link	c.2989A>G	p.Asn997Asp	missense_variant	Exon 20 of 20	ENST00000650623.2	NP_055752.1	Q9Y2H2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5F	ENST00000650623.2 link	c.2989A>G	p.Asn997Asp	missense_variant	Exon 20 of 20		NM_014937.4	ENSP00000497527.1		Q9Y2H2-1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

46243

AN:

151984

Hom.:

7203

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.445

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.285

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.272

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.338

Gnomad OTH

AF:

0.311

GnomAD2 exomes

AF:

0.294

AC:

73838

AN:

251324

AF XY:

0.295

show subpopulations

Gnomad AFR exome

AF:

0.264

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.273

Gnomad EAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.348

Gnomad NFE exome

AF:

0.329

Gnomad OTH exome

AF:

0.312

GnomAD4 exome

AF:

0.328

AC:

479499

AN:

1461702

Hom.:

80222

Cov.:

AF XY:

0.325

AC XY:

236605

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.262

AC:

8782

AN:

33474

American (AMR)

AF:

0.248

AC:

11083

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

7338

AN:

26130

East Asian (EAS)

AF:

0.188

AC:

7444

AN:

39698

South Asian (SAS)

AF:

0.263

AC:

22682

AN:

86258

European-Finnish (FIN)

AF:

0.348

AC:

18582

AN:

53412

Middle Eastern (MID)

AF:

0.309

AC:

1781

AN:

5768

European-Non Finnish (NFE)

AF:

0.344

AC:

382603

AN:

1111846

Other (OTH)

AF:

0.318

AC:

19204

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

19263

38527

57790

77054

96317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.304

AC:

46259

AN:

152102

Hom.:

7209

Cov.:

AF XY:

0.302

AC XY:

22455

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.261

AC:

10849

AN:

41502

American (AMR)

AF:

0.283

AC:

4330

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

988

AN:

3468

East Asian (EAS)

AF:

0.195

AC:

1009

AN:

5180

South Asian (SAS)

AF:

0.271

AC:

1308

AN:

4818

European-Finnish (FIN)

AF:

0.345

AC:

3654

AN:

10588

Middle Eastern (MID)

AF:

0.349

AC:

102

AN:

292

European-Non Finnish (NFE)

AF:

0.338

AC:

22962

AN:

67958

Other (OTH)

AF:

0.309

AC:

653

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1643

3286

4929

6572

8215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.320

Hom.:

26530

Bravo

AF:

0.300

TwinsUK

AF:

0.339

AC:

1257

ALSPAC

AF:

0.348

AC:

1341

ESP6500AA

AF:

0.264

AC:

1164

ESP6500EA

AF:

0.331

AC:

2849

ExAC

AF:

0.293

AC:

35523

Asia WGS

AF:

0.252

AC:

873

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28296976) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.6

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.081

T;T;.;.;.;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.22

.;T;T;.;T;.;T

MetaRNN

Benign

0.0041

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

N;N;.;.;.;.;.

PhyloP100

1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

0.060

N;.;.;.;.;N;.

REVEL

Benign

0.11

Sift

Benign

0.21

T;.;.;.;.;T;.

Sift4G

Benign

0.58

T;.;.;.;.;T;.

Polyphen

0.0

B;B;.;.;.;.;.

Vest4

0.031

MPC

0.14

ClinPred

0.0038

GERP RS

1.9

Varity_R

0.063

gMVP

0.053

Mutation Taster

=97/3

polymorphism (auto)

(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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chr10-119827370-A-G

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