14-72974898-C-T

Position:

• chr14-72974898-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_021260.4(ZFYVE1):​c.1868G>A​(p.Cys623Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFYVE1 NM_021260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ZFYV1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE1	NM_021260.4	c.1868G>A	p.Cys623Tyr	missense_variant	10/12	ENST00000556143.6	NP_067083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE1	ENST00000556143.6	c.1868G>A	p.Cys623Tyr	missense_variant	10/12	1	NM_021260.4	ENSP00000450742.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.1868G>A (p.C623Y) alteration is located in exon 10 (coding exon 9) of the ZFYVE1 gene. This alteration results from a G to A substitution at nucleotide position 1868, causing the cysteine (C) at amino acid position 623 to be replaced by a tyrosine (Y). 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	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.;D;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.8	.;.;H;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.92
MutPred		0.97		Loss of disorder (P = 0.0667);.;Loss of disorder (P = 0.0667);.;.;
MVP		0.95
MPC		2.8
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.93
gMVP		1.0

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.

Other links and lift over

hg19: chr14-73441606;