14-72975718-C-A

Variant names:

• chr14-72975718-C-A
• rs1893152060
• NM_021260.4:c.1639G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021260.4(ZFYVE1):​c.1639G>T​(p.Asp547Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZFYVE1 NM_021260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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]

ACMG classification

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, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE1	NM_021260.4	c.1639G>T	p.Asp547Tyr	missense_variant	Exon 9 of 12	ENST00000556143.6	NP_067083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE1	ENST00000556143.6	c.1639G>T	p.Asp547Tyr	missense_variant	Exon 9 of 12	1	NM_021260.4	ENSP00000450742.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1639G>T (p.D547Y) alteration is located in exon 9 (coding exon 8) of the ZFYVE1 gene. This alteration results from a G to T substitution at nucleotide position 1639, causing the aspartic acid (D) at amino acid position 547 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	Benign	0.20
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T;.;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.7	.;.;L;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.98	D;.;P;.;.
Vest4		0.75
MutPred		0.51		Gain of methylation at K551 (P = 0.0432);.;Gain of methylation at K551 (P = 0.0432);.;.;
MVP		0.64
MPC		1.3
ClinPred		0.91	D
GERP RS		6.2
Varity_R		0.38
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1893152060; hg19: chr14-73442426;