Variant 4-2274196-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020972.3(ZFYVE28):c.2072G>A(p.Cys691Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ZFYVE28
NM_020972.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16994464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE28	NM_020972.3 link	c.2072G>A	p.Cys691Tyr	missense_variant	9/13	ENST00000290974.7	NP_066023.2	Q9HCC9-1
ZFYVE28	NM_001172656.2 link	c.1982G>A	p.Cys661Tyr	missense_variant	8/12		NP_001166127.1	Q9HCC9-2
ZFYVE28	NM_001172659.2 link	c.1862G>A	p.Cys621Tyr	missense_variant	9/13		NP_001166130.1	Q9HCC9-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZFYVE28	ENST00000290974.7 link	c.2072G>A	p.Cys691Tyr	missense_variant	9/13	1	NM_020972.3	ENSP00000290974.3	Q9HCC9-1
ZFYVE28	ENST00000508471.5 link	c.-14G>A		5_prime_UTR_variant	3/7	1		ENSP00000427654.1	Q49AA1
ZFYVE28	ENST00000511071.5 link	c.1982G>A	p.Cys661Tyr	missense_variant	8/12	5		ENSP00000425706.1	Q9HCC9-2
ZFYVE28	ENST00000515312.5 link	c.1862G>A	p.Cys621Tyr	missense_variant	9/13	2		ENSP00000426299.1	Q9HCC9-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000800

AC:

AN:

249860

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461316

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726928

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Nov 11, 2024

The c.2072G>A (p.C691Y) alteration is located in exon 9 (coding exon 9) of the ZFYVE28 gene. This alteration results from a G to A substitution at nucleotide position 2072, causing the cysteine (C) at amino acid position 691 to be replaced by a tyrosine (Y). 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

0.099

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.054

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Benign

0.15

Sift

Benign

0.11

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.94

P;P;.

Vest4

0.23

MutPred

0.19

Gain of phosphorylation at C691 (P = 0.0189);.;.;

MVP

0.31

MPC

0.21

ClinPred

0.47

GERP RS

2.8

Varity_R

0.19

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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