4-2270834-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020972.3(ZFYVE28):c.2555C>T(p.Ser852Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZFYVE28 NM_020972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

Genes affected

ZFYVE28 (HGNC:29334): (zinc finger FYVE-type containing 28) Enables phosphatidylinositol-3-phosphate binding activity. Involved in negative regulation of epidermal growth factor-activated receptor activity. Located in cytosol and early endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE28	NM_020972.3	c.2555C>T	p.Ser852Leu	missense_variant	13/13	ENST00000290974.7
ZFYVE28	NM_001172656.2	c.2465C>T	p.Ser822Leu	missense_variant	12/12
ZFYVE28	NM_001172659.2	c.2345C>T	p.Ser782Leu	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE28	ENST00000290974.7	c.2555C>T	p.Ser852Leu	missense_variant	13/13	1	NM_020972.3	P2
ZFYVE28	ENST00000508471.5	c.470C>T	p.Ser157Leu	missense_variant	7/7	1		A2
ZFYVE28	ENST00000511071.5	c.2465C>T	p.Ser822Leu	missense_variant	12/12	5		A2
ZFYVE28	ENST00000515312.5	c.2345C>T	p.Ser782Leu	missense_variant	13/13	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460626 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726650

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: 0.0000232

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

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

Feb 05, 2024

The c.2555C>T (p.S852L) alteration is located in exon 13 (coding exon 13) of the ZFYVE28 gene. This alteration results from a C to T substitution at nucleotide position 2555, causing the serine (S) at amino acid position 852 to be replaced by a leucine (L). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.058	T;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		1.0, 0.98	.;D;D;.
Vest4		0.44
MutPred		0.52		.;Loss of disorder (P = 0.0094);.;.;
MVP		0.58
MPC		0.25
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.65
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1367189870; hg19: chr4-2272561; COSMIC: COSV104393799; COSMIC: COSV104393799;