Variant 4-2304403-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020972.3(ZFYVE28):c.1937C>T(p.Ala646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

ZFYVE28
NM_020972.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038782418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZFYVE28	NM_020972.3 linkuse as main transcript	c.1937C>T	p.Ala646Val	missense_variant	8/13	ENST00000290974.7	NP_066023.2
ZFYVE28	NM_001172656.2 linkuse as main transcript	c.1847C>T	p.Ala616Val	missense_variant	7/12		NP_001166127.1
ZFYVE28	NM_001172659.2 linkuse as main transcript	c.1727C>T	p.Ala576Val	missense_variant	8/13		NP_001166130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE28	ENST00000290974.7 linkuse as main transcript	c.1937C>T	p.Ala646Val	missense_variant	8/13	1	NM_020972.3	ENSP00000290974	P2	Q9HCC9-1
	ENST00000510632.1 linkuse as main transcript	n.263-2488G>A		intron_variant, non_coding_transcript_variant		4
ZFYVE28	ENST00000511071.5 linkuse as main transcript	c.1847C>T	p.Ala616Val	missense_variant	7/12	5		ENSP00000425706	A2	Q9HCC9-2
ZFYVE28	ENST00000515312.5 linkuse as main transcript	c.1727C>T	p.Ala576Val	missense_variant	8/13	2		ENSP00000426299	A2	Q9HCC9-3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000184

AC:

AN:

250592

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000146

AC:

213

AN:

1460922

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000580

Gnomad4 FIN exome

AF:

0.0000381

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000145

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

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

Dec 23, 2022

The c.1937C>T (p.A646V) alteration is located in exon 8 (coding exon 8) of the ZFYVE28 gene. This alteration results from a C to T substitution at nucleotide position 1937, causing the alanine (A) at amino acid position 646 to be replaced by a valine (V). 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

Benign

0.086

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.71

T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.039

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.063

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.61

T;T;T

Polyphen

0.84

P;P;.

Vest4

0.077

MVP

0.35

MPC

0.046

ClinPred

0.038

GERP RS

2.5

Varity_R

0.067

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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