rs1529979

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 13/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIKFYVE. . Gene score misZ 2.0469 (greater than the threshold 3.09). Trascript score misZ 3.5403 (greater than threshold 3.09). GenCC has associacion of gene with fleck corneal dystrophy.

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 id is 333917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208326358-C-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIKFYVE	NM_015040.4 linkuse as main transcript	c.3547C>A	p.Gln1183Lys	missense_variant	20/42	ENST00000264380.9	NP_055855.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIKFYVE	ENST00000264380.9 linkuse as main transcript	c.3547C>A	p.Gln1183Lys	missense_variant	20/42	1	NM_015040.4	ENSP00000264380	P1	Q9Y2I7-1
PIKFYVE	ENST00000452564.1 linkuse as main transcript	c.3379C>A	p.Gln1127Lys	missense_variant	19/25	2		ENSP00000405736

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

GnomAD3 exomes

AF:

0.964

AC:

241498

AN:

250408

Hom.:

116777

AF XY:

0.966

AC XY:

130723

AN XY:

135284

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 SAS exome

AF:

0.939

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

Gnomad4 AFR exome

AF:

0.795

Gnomad4 AMR exome

AF:

0.982

Gnomad4 ASJ exome

AF:

0.996

Gnomad4 EAS exome

AF:

0.957

Gnomad4 SAS exome

AF:

0.941

Gnomad4 FIN exome

AF:

0.996

Gnomad4 NFE exome

AF:

0.984

Gnomad4 OTH exome

AF:

0.969

GnomAD4 genome

AF:

0.930

AC:

141624

AN:

152264

Hom.:

66385

Cov.:

AF XY:

0.932

AC XY:

69410

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.802

Gnomad4 AMR

AF:

0.970

Gnomad4 ASJ

AF:

0.996

Gnomad4 EAS

AF:

0.944

Gnomad4 SAS

AF:

0.933

Gnomad4 FIN

AF:

0.997

Gnomad4 NFE

AF:

0.983

Gnomad4 OTH

AF:

0.941

Alfa

AF:

0.970

Hom.:

120128

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fleck corneal dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.16

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

6.3e-7

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.81

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.17

N;N

REVEL

Benign

0.055

Sift

Benign

1.0

T;T

Sift4G

Benign

0.97

T;T

Polyphen

0.0

B;B

Vest4

0.031

MPC

0.36

ClinPred

0.00077

GERP RS

4.7

Varity_R

0.058

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over