Variant 1-52238418-G-T 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_004799.4(ZFYVE9):c.1001G>T(p.Arg334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,762 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: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZFYVE9
NM_004799.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.760

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:

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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=0.02546075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE9	NM_004799.4 linkuse as main transcript	c.1001G>T	p.Arg334Leu	missense_variant	4/19	ENST00000287727.8	NP_004790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE9	ENST00000287727.8 linkuse as main transcript	c.1001G>T	p.Arg334Leu	missense_variant	4/19	5	NM_004799.4	ENSP00000287727	P1	O95405-1
ZFYVE9	ENST00000371591.2 linkuse as main transcript	c.1001G>T	p.Arg334Leu	missense_variant	5/20	1		ENSP00000360647	P1	O95405-1
ZFYVE9	ENST00000357206.6 linkuse as main transcript	c.1001G>T	p.Arg334Leu	missense_variant	4/18	1		ENSP00000349737		O95405-2
ZFYVE9	ENST00000361625.5 linkuse as main transcript	n.1173G>T		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727180

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Apr 13, 2022

The c.1001G>T (p.R334L) alteration is located in exon 4 (coding exon 2) of the ZFYVE9 gene. This alteration results from a G to T substitution at nucleotide position 1001, causing the arginine (R) at amino acid position 334 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

Benign

0.067

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.046

DANN

Benign

0.79

DEOGEN2

Benign

0.0026

T;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.65

T;T;.

M_CAP

Benign

0.0035

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.86

N;N;N

REVEL

Benign

0.014

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.67

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.16

MutPred

0.19

Loss of glycosylation at S335 (P = 0.1582);Loss of glycosylation at S335 (P = 0.1582);Loss of glycosylation at S335 (P = 0.1582);

MVP

0.043

MPC

0.13

ClinPred

0.078

GERP RS

-9.5

Varity_R

0.028

gMVP

0.14

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over