Variant chr4-2304322-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020972.3(ZFYVE28):c.2018C>T(p.Ala673Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZFYVE28
NM_020972.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.392

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:

ENSG00000251148 (HGNC:):

ENSG00000251148 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39336517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE28	NM_020972.3 link	c.2018C>T	p.Ala673Val	missense_variant	8/13	ENST00000290974.7	NP_066023.2	Q9HCC9-1
ZFYVE28	NM_001172656.2 link	c.1928C>T	p.Ala643Val	missense_variant	7/12		NP_001166127.1	Q9HCC9-2
ZFYVE28	NM_001172659.2 link	c.1808C>T	p.Ala603Val	missense_variant	8/13		NP_001166130.1	Q9HCC9-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZFYVE28	ENST00000290974.7 link	c.2018C>T	p.Ala673Val	missense_variant	8/13	1	NM_020972.3	ENSP00000290974.3	Q9HCC9-1
ZFYVE28	ENST00000511071.5 link	c.1928C>T	p.Ala643Val	missense_variant	7/12	5		ENSP00000425706.1	Q9HCC9-2
ZFYVE28	ENST00000515312.5 link	c.1808C>T	p.Ala603Val	missense_variant	8/13	2		ENSP00000426299.1	Q9HCC9-3
ENSG00000251148	ENST00000510632.1 link	n.263-2569G>A		intron_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000419

AC:

AN:

238884

Hom.:

AF XY:

0.00000766

AC XY:

AN XY:

130606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448264

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000333

Hom.:

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 14, 2023

The c.2018C>T (p.A673V) 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 2018, causing the alanine (A) at amino acid position 673 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

0.074

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.6

DANN

Benign

0.96

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.65

T;T;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.063

Sift

Benign

0.080

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.047

B;B;.

Vest4

0.085

MutPred

0.19

Loss of glycosylation at P671 (P = 0.0718);.;.;

MVP

0.37

MPC

0.044

ClinPred

0.034

GERP RS

-0.77

Varity_R

0.032

gMVP

0.19

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