Variant chr14-72998096-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_021260.4(ZFYVE1):c.703G>A(p.Asp235Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,870 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: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZFYVE1
NM_021260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

ZFYVE1 (HGNC:13180): (zinc finger FYVE-type containing 1) The FYVE domain mediates the recruitment of proteins involved in membrane trafficking and cell signaling to phosphatidylinositol 3-phosphate-containing membranes. This protein contains two zinc-binding FYVE domains in tandem and is reported to localize to the Golgi apparatus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ZFYVE1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE1	NM_021260.4 linkuse as main transcript	c.703G>A	p.Asp235Asn	missense_variant	3/12	ENST00000556143.6	NP_067083.1	Q9HBF4-1
ZFYVE1	NM_001281734.2 linkuse as main transcript	c.703G>A	p.Asp235Asn	missense_variant	3/12		NP_001268663.1	Q9HBF4-3
ZFYVE1	XM_047431481.1 linkuse as main transcript	c.703G>A	p.Asp235Asn	missense_variant	3/7		XP_047287437.1
ZFYVE1	XM_047431482.1 linkuse as main transcript	c.-543G>A		5_prime_UTR_variant	3/12		XP_047287438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZFYVE1	ENST00000556143.6 linkuse as main transcript	c.703G>A	p.Asp235Asn	missense_variant	3/12	1	NM_021260.4	ENSP00000450742.1	Q9HBF4-1
ZFYVE1	ENST00000318876.9 linkuse as main transcript	c.703G>A	p.Asp235Asn	missense_variant	3/12	1		ENSP00000326921.5	Q9HBF4-3
ZFYVE1	ENST00000553891.5 linkuse as main transcript	c.703G>A	p.Asp235Asn	missense_variant	3/13	5		ENSP00000452442.1	G3V5N8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251370

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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 02, 2022

The c.703G>A (p.D235N) alteration is located in exon 3 (coding exon 2) of the ZFYVE1 gene. This alteration results from a G to A substitution at nucleotide position 703, causing the aspartic acid (D) at amino acid position 235 to be replaced by an asparagine (N). 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

1.0

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;.;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

.;M;M

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.85

MutPred

0.68

Gain of ubiquitination at K230 (P = 0.0846);Gain of ubiquitination at K230 (P = 0.0846);Gain of ubiquitination at K230 (P = 0.0846);

MVP

0.86

MPC

0.99

ClinPred

0.99

GERP RS

5.8

Varity_R

0.74

gMVP

0.96

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