Variant 4-2270846-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 NM_020972.3(ZFYVE28):c.2543C>T(p.Ser848Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,536 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: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ZFYVE28
NM_020972.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.48

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:

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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, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE28	NM_020972.3 link	c.2543C>T	p.Ser848Leu	missense_variant	13/13	ENST00000290974.7	NP_066023.2	Q9HCC9-1
ZFYVE28	NM_001172656.2 link	c.2453C>T	p.Ser818Leu	missense_variant	12/12		NP_001166127.1	Q9HCC9-2
ZFYVE28	NM_001172659.2 link	c.2333C>T	p.Ser778Leu	missense_variant	13/13		NP_001166130.1	Q9HCC9-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZFYVE28	ENST00000290974.7 link	c.2543C>T	p.Ser848Leu	missense_variant	13/13	1	NM_020972.3	ENSP00000290974.3	Q9HCC9-1
ZFYVE28	ENST00000508471.5 link	c.458C>T	p.Ser153Leu	missense_variant	7/7	1		ENSP00000427654.1	Q49AA1
ZFYVE28	ENST00000511071.5 link	c.2453C>T	p.Ser818Leu	missense_variant	12/12	5		ENSP00000425706.1	Q9HCC9-2
ZFYVE28	ENST00000515312.5 link	c.2333C>T	p.Ser778Leu	missense_variant	13/13	2		ENSP00000426299.1	Q9HCC9-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248364

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134950

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:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000959

AC:

AN:

1460536

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726594

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:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

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 10, 2024

The c.2543C>T (p.S848L) alteration is located in exon 13 (coding exon 13) of the ZFYVE28 gene. This alteration results from a C to T substitution at nucleotide position 2543, causing the serine (S) at amino acid position 848 to be replaced by a leucine (L). 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

0.90

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

-0.033

MutationAssessor

Pathogenic

3.4

.;M;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.1

D;D;D;D

REVEL

Uncertain

0.51

Sift

Benign

0.056

T;D;D;D

Sift4G

Uncertain

0.037

D;T;T;D

Polyphen

1.0, 1.0

.;D;D;.

Vest4

0.75

MutPred

0.62

.;Loss of disorder (P = 0.0061);.;.;

MVP

0.60

MPC

0.30

ClinPred

0.99

GERP RS

4.5

Varity_R

0.68

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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