NM_015040.4:c.5397A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015040.4(PIKFYVE):c.5397A>G(p.Thr1799Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 1,611,464 control chromosomes in the GnomAD database, including 762,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.93 ( 66259 hom., cov: 31)

Exomes 𝑓: 0.98 ( 696154 hom. )

Consequence

PIKFYVE
NM_015040.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.87

Publications

24 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

PIKFYVE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 2-208350046-A-G is Benign according to our data. Variant chr2-208350046-A-G is described in ClinVar as Benign. ClinVar VariationId is 333932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.87 with no splicing effect.

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.5397A>G	p.Thr1799Thr	synonymous	Exon 36 of 42	NP_055855.2	Q9Y2I7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIKFYVE	ENST00000264380.9	TSL:1 MANE Select	c.5397A>G	p.Thr1799Thr	synonymous	Exon 36 of 42	ENSP00000264380.4	Q9Y2I7-1
PIKFYVE	ENST00000909798.1		c.5412A>G	p.Thr1804Thr	synonymous	Exon 37 of 43	ENSP00000579857.1
PIKFYVE	ENST00000923116.1		c.5379A>G	p.Thr1793Thr	synonymous	Exon 36 of 42	ENSP00000593175.1

Frequencies

GnomAD3 genomes

AF:

0.930

AC:

141301

AN:

152010

Hom.:

66208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.800

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.970

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.943

Gnomad SAS

AF:

0.931

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.975

Gnomad NFE

AF:

0.983

Gnomad OTH

AF:

0.939

GnomAD2 exomes

AF:

0.964

AC:

241826

AN:

250756

AF XY:

0.966

show subpopulations

Gnomad AFR exome

AF:

0.798

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:

1424603

AN:

1459336

Hom.:

696154

Cov.:

AF XY:

0.976

AC XY:

708565

AN XY:

726010

show subpopulations

African (AFR)

AF:

0.793

AC:

26503

AN:

33414

American (AMR)

AF:

0.982

AC:

43839

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

25941

AN:

26036

East Asian (EAS)

AF:

0.957

AC:

37786

AN:

39500

South Asian (SAS)

AF:

0.941

AC:

81004

AN:

86082

European-Finnish (FIN)

AF:

0.996

AC:

53059

AN:

53286

Middle Eastern (MID)

AF:

0.964

AC:

5540

AN:

5748

European-Non Finnish (NFE)

AF:

0.984

AC:

1092554

AN:

1110398

Other (OTH)

AF:

0.969

AC:

58377

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

1975

3949

5924

7898

9873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21642

43284

64926

86568

108210

<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:

141410

AN:

152128

Hom.:

66259

Cov.:

AF XY:

0.932

AC XY:

69324

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.800

AC:

33189

AN:

41468

American (AMR)

AF:

0.970

AC:

14833

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3457

AN:

3472

East Asian (EAS)

AF:

0.943

AC:

4889

AN:

5182

South Asian (SAS)

AF:

0.933

AC:

4491

AN:

4816

European-Finnish (FIN)

AF:

0.997

AC:

10560

AN:

10590

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.983

AC:

66813

AN:

67986

Other (OTH)

AF:

0.939

AC:

1984

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

462

925

1387

1850

2312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.972

Hom.:

111844

Bravo

AF:

0.922

Asia WGS

AF:

0.930

AC:

3230

AN:

3474

ClinVar

ClinVar submissions

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

BayesDel_noAF

Benign

-0.59

CADD

Benign

9.8

(source)

DANN

Benign

0.69

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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