rs1529979

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_015040.4(PIKFYVE):c.3547C>A(p.Gln1183Lys) variant causes a missense change. The variant allele was found at a frequency of 0.972 in 1,613,836 control chromosomes in the GnomAD database, including 763,665 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66385 hom., cov: 31)

Exomes 𝑓: 0.98 ( 697280 hom. )

Consequence

PIKFYVE
NM_015040.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.40

Publications

32 publications found

Variant links:

Genes affected

PIKFYVE (HGNC:23785): (phosphoinositide kinase, FYVE-type zinc finger containing) Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell- and endosomal-membranes. Humans have multiple PtdIns proteins that differ by the degree and position of phosphorylation of the inositol ring. This gene encodes an enzyme (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) that phosphorylates the D-5 position in PtdIns and phosphatidylinositol-3-phosphate (PtdIns3P) to make PtdIns5P and PtdIns(3,5)biphosphate. The D-5 position also can be phosphorylated by type I PtdIns4P-5-kinases (PIP5Ks) that are encoded by distinct genes and preferentially phosphorylate D-4 phosphorylated PtdIns. In contrast, PIKfyve preferentially phosphorylates D-3 phosphorylated PtdIns. In addition to being a lipid kinase, PIKfyve also has protein kinase activity. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The protein plays a key role in cell entry of ebola virus and SARS-CoV-2 by endocytosis Mutations in this gene cause corneal fleck dystrophy (CFD); an autosomal dominant disorder characterized by numerous small white flecks present in all layers of the corneal stroma. Histologically, these flecks appear to be keratocytes distended with lipid and mucopolysaccharide filled intracytoplasmic vacuoles. [provided by RefSeq, Jul 2021]

PIKFYVE Gene-Disease associations (from GenCC):

fleck corneal dystrophy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

PIKFYVE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=6.253979E-7).

BP6

Variant 2-208326358-C-A is Benign according to our data. Variant chr2-208326358-C-A is described in ClinVar as Benign. ClinVar VariationId is 333917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015040.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIKFYVE	NM_015040.4	MANE Select	c.3547C>A	p.Gln1183Lys	missense	Exon 20 of 42	NP_055855.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIKFYVE	ENST00000264380.9	TSL:1 MANE Select	c.3547C>A	p.Gln1183Lys	missense	Exon 20 of 42	ENSP00000264380.4
PIKFYVE	ENST00000909798.1		c.3562C>A	p.Gln1188Lys	missense	Exon 21 of 43	ENSP00000579857.1
PIKFYVE	ENST00000923116.1		c.3529C>A	p.Gln1177Lys	missense	Exon 20 of 42	ENSP00000593175.1

Frequencies

GnomAD3 genomes

AF:

0.930

AC:

141514

AN:

152146

Hom.:

66333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.802

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.970

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.944

Gnomad SAS

AF:

0.932

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.983

Gnomad OTH

AF:

0.940

GnomAD2 exomes

AF:

0.964

AC:

241498

AN:

250408

AF XY:

0.966

show subpopulations

Gnomad AFR exome

AF:

0.799

Gnomad AMR exome

AF:

0.985

Gnomad ASJ exome

AF:

0.997

Gnomad EAS exome

AF:

0.940

Gnomad FIN exome

AF:

0.997

Gnomad NFE exome

AF:

0.983

Gnomad OTH exome

AF:

0.977

GnomAD4 exome

AF:

0.976

AC:

1426863

AN:

1461572

Hom.:

697280

Cov.:

AF XY:

0.976

AC XY:

709657

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.795

AC:

26618

AN:

33464

American (AMR)

AF:

0.982

AC:

43877

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

26024

AN:

26120

East Asian (EAS)

AF:

0.957

AC:

37975

AN:

39696

South Asian (SAS)

AF:

0.941

AC:

81081

AN:

86168

European-Finnish (FIN)

AF:

0.996

AC:

53179

AN:

53406

Middle Eastern (MID)

AF:

0.964

AC:

5561

AN:

5768

European-Non Finnish (NFE)

AF:

0.984

AC:

1094034

AN:

1111904

Other (OTH)

AF:

0.969

AC:

58514

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1829

3657

5486

7314

9143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21650

43300

64950

86600

108250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.930

AC:

141624

AN:

152264

Hom.:

66385

Cov.:

AF XY:

0.932

AC XY:

69410

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.802

AC:

33301

AN:

41508

American (AMR)

AF:

0.970

AC:

14836

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3457

AN:

3472

East Asian (EAS)

AF:

0.944

AC:

4883

AN:

5174

South Asian (SAS)

AF:

0.933

AC:

4502

AN:

4826

European-Finnish (FIN)

AF:

0.997

AC:

10596

AN:

10626

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.983

AC:

66870

AN:

68044

Other (OTH)

AF:

0.941

AC:

1985

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

465

929

1394

1858

2323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.966

Hom.:

177049

Bravo

AF:

0.922

TwinsUK

AF:

0.986

AC:

3657

ALSPAC

AF:

0.984

AC:

3794

ESP6500AA

AF:

0.807

AC:

3554

ESP6500EA

AF:

0.982

AC:

8442

ExAC

AF:

0.960

AC:

116510

Asia WGS

AF:

0.930

AC:

3236

AN:

3478

EpiCase

AF:

0.983

EpiControl

AF:

0.985

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fleck corneal dystrophy (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.13

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.15

MetaRNN

Benign

6.3e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.81

PhyloP100

4.4

PrimateAI

Benign

0.32

PROVEAN

Benign

0.17

REVEL

Benign

0.055

Sift

Benign

1.0

Sift4G

Benign

0.97

Polyphen

0.0

Vest4

0.031

MPC

0.36

ClinPred

0.00077

GERP RS

4.7

Varity_R

0.058

gMVP

0.26

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over