rs2304545

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_015040.4(PIKFYVE):c.5334G>A(p.Thr1778Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,613,796 control chromosomes in the GnomAD database, including 552,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 42354 hom., cov: 32)

Exomes 𝑓: 0.83 ( 510425 hom. )

Consequence

PIKFYVE
NM_015040.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.549

Publications

25 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 2-208347983-G-A is Benign according to our data. Variant chr2-208347983-G-A is described in ClinVar as Benign. ClinVar VariationId is 333930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.549 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.876 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.5334G>A	p.Thr1778Thr	synonymous	Exon 35 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.5334G>A	p.Thr1778Thr	synonymous	Exon 35 of 42	ENSP00000264380.4	Q9Y2I7-1
PIKFYVE	ENST00000909798.1		c.5349G>A	p.Thr1783Thr	synonymous	Exon 36 of 43	ENSP00000579857.1
PIKFYVE	ENST00000923116.1		c.5316G>A	p.Thr1772Thr	synonymous	Exon 35 of 42	ENSP00000593175.1

Frequencies

GnomAD3 genomes

AF:

0.715

AC:

108730

AN:

152010

Hom.:

42341

Cov.:

show subpopulations

Gnomad AFR

AF:

0.374

Gnomad AMI

AF:

0.914

Gnomad AMR

AF:

0.820

Gnomad ASJ

AF:

0.861

Gnomad EAS

AF:

0.898

Gnomad SAS

AF:

0.818

Gnomad FIN

AF:

0.899

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.837

Gnomad OTH

AF:

0.756

GnomAD2 exomes

AF:

0.823

AC:

207006

AN:

251456

AF XY:

0.829

show subpopulations

Gnomad AFR exome

AF:

0.364

Gnomad AMR exome

AF:

0.887

Gnomad ASJ exome

AF:

0.868

Gnomad EAS exome

AF:

0.900

Gnomad FIN exome

AF:

0.898

Gnomad NFE exome

AF:

0.841

Gnomad OTH exome

AF:

0.840

GnomAD4 exome

AF:

0.832

AC:

1216009

AN:

1461672

Hom.:

510425

Cov.:

AF XY:

0.833

AC XY:

605774

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.354

AC:

11850

AN:

33472

American (AMR)

AF:

0.879

AC:

39327

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.872

AC:

22787

AN:

26132

East Asian (EAS)

AF:

0.917

AC:

36403

AN:

39694

South Asian (SAS)

AF:

0.814

AC:

70220

AN:

86252

European-Finnish (FIN)

AF:

0.894

AC:

47743

AN:

53416

Middle Eastern (MID)

AF:

0.826

AC:

4763

AN:

5764

European-Non Finnish (NFE)

AF:

0.840

AC:

933814

AN:

1111832

Other (OTH)

AF:

0.813

AC:

49102

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

11069

22138

33206

44275

55344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21008

42016

63024

84032

105040

<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:

0.715

AC:

108765

AN:

152124

Hom.:

42354

Cov.:

AF XY:

0.723

AC XY:

53768

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.374

AC:

15497

AN:

41442

American (AMR)

AF:

0.821

AC:

12538

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.861

AC:

2990

AN:

3472

East Asian (EAS)

AF:

0.898

AC:

4651

AN:

5182

South Asian (SAS)

AF:

0.820

AC:

3953

AN:

4818

European-Finnish (FIN)

AF:

0.899

AC:

9524

AN:

10596

Middle Eastern (MID)

AF:

0.837

AC:

246

AN:

294

European-Non Finnish (NFE)

AF:

0.837

AC:

56930

AN:

68016

Other (OTH)

AF:

0.759

AC:

1602

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1264

2528

3793

5057

6321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.731

Hom.:

35412

Bravo

AF:

0.696

Asia WGS

AF:

0.821

AC:

2856

AN:

3478

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

-0.30

CADD

Benign

4.9

(source)

DANN

Benign

0.64

PhyloP100

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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