14-72993174-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_021260.4(ZFYVE1):​c.1172G>A​(p.Arg391Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,988 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: 30)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZFYVE1
NM_021260.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81
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]

Genome browser will be placed here

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, 0.824

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZFYVE1NM_021260.4 linkc.1172G>A p.Arg391Gln missense_variant Exon 4 of 12 ENST00000556143.6 NP_067083.1 Q9HBF4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZFYVE1ENST00000556143.6 linkc.1172G>A p.Arg391Gln missense_variant Exon 4 of 12 1 NM_021260.4 ENSP00000450742.1 Q9HBF4-1
ZFYVE1ENST00000318876.9 linkc.1172G>A p.Arg391Gln missense_variant Exon 4 of 12 1 ENSP00000326921.5 Q9HBF4-3
ZFYVE1ENST00000553891.5 linkc.1172G>A p.Arg391Gln missense_variant Exon 4 of 13 5 ENSP00000452442.1 G3V5N8

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1459988
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726192
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 13, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1172G>A (p.R391Q) alteration is located in exon 4 (coding exon 3) of the ZFYVE1 gene. This alteration results from a G to A substitution at nucleotide position 1172, causing the arginine (R) at amino acid position 391 to be replaced by a glutamine (Q). 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
0.97
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
T;.;T
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Uncertain
2.7
.;M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.85
MutPred
0.45
Loss of catalytic residue at R391 (P = 0.0586);Loss of catalytic residue at R391 (P = 0.0586);Loss of catalytic residue at R391 (P = 0.0586);
MVP
0.61
MPC
1.1
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.78
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs759215529; hg19: chr14-73459882; COSMIC: COSV59610270; API