14-72997852-A-G

Position:

• chr14-72997852-A-G

Variant summary

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

The NM_021260.4(ZFYVE1):​c.947T>C​(p.Ile316Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,742 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: 0.0000028 (0 hom.)
• Consequence: ZFYVE1 NM_021260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.24

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, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE1	NM_021260.4	c.947T>C	p.Ile316Thr	missense_variant	3/12	ENST00000556143.6	NP_067083.1
ZFYVE1	NM_001281734.2	c.947T>C	p.Ile316Thr	missense_variant	3/12		NP_001268663.1
ZFYVE1	XM_047431481.1	c.947T>C	p.Ile316Thr	missense_variant	3/7		XP_047287437.1
ZFYVE1	XM_047431482.1	c.-299T>C		5_prime_UTR_variant	3/12		XP_047287438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE1	ENST00000556143.6	c.947T>C	p.Ile316Thr	missense_variant	3/12	1	NM_021260.4	ENSP00000450742.1
ZFYVE1	ENST00000318876.9	c.947T>C	p.Ile316Thr	missense_variant	3/12	1		ENSP00000326921.5
ZFYVE1	ENST00000553891.5	c.947T>C	p.Ile316Thr	missense_variant	3/13	5		ENSP00000452442.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453742 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721206

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jan 08, 2024

The c.947T>C (p.I316T) alteration is located in exon 3 (coding exon 2) of the ZFYVE1 gene. This alteration results from a T to C substitution at nucleotide position 947, causing the isoleucine (I) at amino acid position 316 to be replaced by a threonine (T). 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	0.68
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.4	.;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;.;D
Vest4		0.85
MutPred		0.58		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.25
MPC		0.62
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.92

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

Other links and lift over

dbSNP: rs1893782571; hg19: chr14-73464560;