Variant 4-2274119-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000290974.7(ZFYVE28):c.2149C>T(p.Arg717Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ZFYVE28
ENST00000290974.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Variant links:

Genes affected

ZFYVE28 (HGNC:29334): (zinc finger FYVE-type containing 28) Enables phosphatidylinositol-3-phosphate binding activity. Involved in negative regulation of epidermal growth factor-activated receptor activity. Located in cytosol and early endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZFYVE28 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZFYVE28	NM_020972.3 linkuse as main transcript	c.2149C>T	p.Arg717Trp	missense_variant	9/13	ENST00000290974.7	NP_066023.2
ZFYVE28	NM_001172656.2 linkuse as main transcript	c.2059C>T	p.Arg687Trp	missense_variant	8/12		NP_001166127.1
ZFYVE28	NM_001172659.2 linkuse as main transcript	c.1939C>T	p.Arg647Trp	missense_variant	9/13		NP_001166130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE28	ENST00000290974.7 linkuse as main transcript	c.2149C>T	p.Arg717Trp	missense_variant	9/13	1	NM_020972.3	ENSP00000290974	P2	Q9HCC9-1
ZFYVE28	ENST00000508471.5 linkuse as main transcript	c.64C>T	p.Arg22Trp	missense_variant	3/7	1		ENSP00000427654	A2
ZFYVE28	ENST00000511071.5 linkuse as main transcript	c.2059C>T	p.Arg687Trp	missense_variant	8/12	5		ENSP00000425706	A2	Q9HCC9-2
ZFYVE28	ENST00000515312.5 linkuse as main transcript	c.1939C>T	p.Arg647Trp	missense_variant	9/13	2		ENSP00000426299	A2	Q9HCC9-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.2149C>T (p.R717W) alteration is located in exon 9 (coding exon 9) of the ZFYVE28 gene. This alteration results from a C to T substitution at nucleotide position 2149, causing the arginine (R) at amino acid position 717 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

T;T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.72

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.0

.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.0

D;D;D;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.88

MutPred

0.55

.;Loss of disorder (P = 0.018);.;.;

MVP

0.50

MPC

0.31

ClinPred

1.0

GERP RS

2.8

Varity_R

0.74

gMVP

0.75

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