4-2304403-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020972.3(ZFYVE28):c.1937C>T(p.Ala646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: ZFYVE28 NM_020972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038782418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE28	NM_020972.3	c.1937C>T	p.Ala646Val	missense_variant	8/13	ENST00000290974.7
ZFYVE28	NM_001172656.2	c.1847C>T	p.Ala616Val	missense_variant	7/12
ZFYVE28	NM_001172659.2	c.1727C>T	p.Ala576Val	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE28	ENST00000290974.7	c.1937C>T	p.Ala646Val	missense_variant	8/13	1	NM_020972.3	P2
	ENST00000510632.1	n.263-2488G>A		intron_variant, non_coding_transcript_variant		4
ZFYVE28	ENST00000511071.5	c.1847C>T	p.Ala616Val	missense_variant	7/12	5		A2
ZFYVE28	ENST00000515312.5	c.1727C>T	p.Ala576Val	missense_variant	8/13	2		A2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 46 AN: 250592 Hom.: 1 AF XY: 0.000236 AC XY: 32 AN XY: 135662

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000146 AC: 213 AN: 1460922 Hom.: 1 Cov.: 42 AF XY: 0.000175 AC XY: 127 AN XY: 726812

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152244 Hom.: 0 Cov.: 34 AF XY: 0.000175 AC XY: 13 AN XY: 74392

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

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 23, 2022

The c.1937C>T (p.A646V) alteration is located in exon 8 (coding exon 8) of the ZFYVE28 gene. This alteration results from a C to T substitution at nucleotide position 1937, causing the alanine (A) at amino acid position 646 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	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.039	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.063
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.61	T;T;T
Polyphen		0.84	P;P;.
Vest4		0.077
MVP		0.35
MPC		0.046
ClinPred		0.038	T
GERP RS		2.5
Varity_R		0.067
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs772852130; hg19: chr4-2306130; COSMIC: COSV99343791;