Variant 1-52238448-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004799.4(ZFYVE9):c.1031A>T(p.Asp344Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,613,994 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ZFYVE9
NM_004799.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

ZFYVE9 (HGNC:6775): (zinc finger FYVE-type containing 9) This gene encodes a double zinc finger motif-containing protein that participates in the transforming growth factor-beta (TGFB) signalling pathway. The encoded protein interacts directly with SMAD2 and SMAD3, and recruits SMAD2 to the TGFB receptor. There are multiple pseudogenes for this gene on chromosomes 2, 15, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ZFYVE9 links:

ZFYVE9 (HGNC:):

ZFYVE9 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07535839).

BS2

High AC in GnomAdExome4 at 210 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE9	NM_004799.4 linkuse as main transcript	c.1031A>T	p.Asp344Val	missense_variant	4/19	ENST00000287727.8	NP_004790.2	O95405-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZFYVE9	ENST00000287727.8 linkuse as main transcript	c.1031A>T	p.Asp344Val	missense_variant	4/19	5	NM_004799.4	ENSP00000287727.3	O95405-1
ZFYVE9	ENST00000371591.2 linkuse as main transcript	c.1031A>T	p.Asp344Val	missense_variant	5/20	1		ENSP00000360647.1	O95405-1
ZFYVE9	ENST00000357206.6 linkuse as main transcript	c.1031A>T	p.Asp344Val	missense_variant	4/18	1		ENSP00000349737.2	O95405-2
ZFYVE9	ENST00000361625.5 linkuse as main transcript	n.1203A>T		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000359

AC:

AN:

250782

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135508

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:

0.0000795

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727212

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:

0.000184

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

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 19, 2022

The c.1031A>T (p.D344V) alteration is located in exon 4 (coding exon 2) of the ZFYVE9 gene. This alteration results from a A to T substitution at nucleotide position 1031, causing the aspartic acid (D) at amino acid position 344 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

0.083

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.021

T;.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.83

T;T;.

M_CAP

Benign

0.0096

MetaRNN

Benign

0.075

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L;L

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.025

D;D;D

Sift4G

Benign

0.24

T;T;T

Polyphen

0.11

B;B;B

Vest4

0.27

MutPred

0.19

Loss of ubiquitination at K342 (P = 0.0211);Loss of ubiquitination at K342 (P = 0.0211);Loss of ubiquitination at K342 (P = 0.0211);

MVP

0.20

MPC

0.18

ClinPred

0.066

GERP RS

3.6

Varity_R

0.097

gMVP

0.26

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