4-2304437-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020972.3(ZFYVE28):c.1903C>G(p.Leu635Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ZFYVE28 NM_020972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.07

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35018772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE28	NM_020972.3	c.1903C>G	p.Leu635Val	missense_variant	8/13	ENST00000290974.7
ZFYVE28	NM_001172656.2	c.1813C>G	p.Leu605Val	missense_variant	7/12
ZFYVE28	NM_001172659.2	c.1693C>G	p.Leu565Val	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE28	ENST00000290974.7	c.1903C>G	p.Leu635Val	missense_variant	8/13	1	NM_020972.3	P2
	ENST00000510632.1	n.263-2454G>C		intron_variant, non_coding_transcript_variant		4
ZFYVE28	ENST00000511071.5	c.1813C>G	p.Leu605Val	missense_variant	7/12	5		A2
ZFYVE28	ENST00000515312.5	c.1693C>G	p.Leu565Val	missense_variant	8/13	2		A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 13, 2022

The c.1903C>G (p.L635V) alteration is located in exon 8 (coding exon 8) of the ZFYVE28 gene. This alteration results from a C to G substitution at nucleotide position 1903, causing the leucine (L) at amino acid position 635 to be replaced by a valine (V). 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	0.098
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.075
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0080	D;D;D
Sift4G	Benign	0.19	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.31
MutPred		0.34		Loss of catalytic residue at L635 (P = 0.0179);.;.;
MVP		0.68
MPC		0.10
ClinPred		0.78	D
GERP RS		3.8
Varity_R		0.11
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-2306164;