4-2304330-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020972.3(ZFYVE28):c.2010C>A(p.Ser670Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,451,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZFYVE28 NM_020972.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.36

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07868743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFYVE28	NM_020972.3	c.2010C>A	p.Ser670Arg	missense_variant	8/13	ENST00000290974.7
ZFYVE28	NM_001172656.2	c.1920C>A	p.Ser640Arg	missense_variant	7/12
ZFYVE28	NM_001172659.2	c.1800C>A	p.Ser600Arg	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFYVE28	ENST00000290974.7	c.2010C>A	p.Ser670Arg	missense_variant	8/13	1	NM_020972.3	P2
	ENST00000510632.1	n.263-2561G>T		intron_variant, non_coding_transcript_variant		4
ZFYVE28	ENST00000511071.5	c.1920C>A	p.Ser640Arg	missense_variant	7/12	5		A2
ZFYVE28	ENST00000515312.5	c.1800C>A	p.Ser600Arg	missense_variant	8/13	2		A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451234 Hom.: 0 Cov.: 42 AF XY: 0.00000554 AC XY: 4 AN XY: 722272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

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

Apr 08, 2022

The c.2010C>A (p.S670R) alteration is located in exon 8 (coding exon 8) of the ZFYVE28 gene. This alteration results from a C to A substitution at nucleotide position 2010, causing the serine (S) at amino acid position 670 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.46
Dann	Benign	0.79
DEOGEN2	Benign	0.014	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.41	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.079	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.11	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.060
MutPred		0.23		Loss of phosphorylation at S670 (P = 0.0121);.;.;
MVP		0.082
MPC		0.047
ClinPred		0.10	T
GERP RS		-1.4
Varity_R		0.082
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs768638735; hg19: chr4-2306057;