1-52238310-G-C

Position:

• chr1-52238310-G-C

Variant summary

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

The NM_004799.4(ZFYVE9):​c.893G>C​(p.Ser298Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: ZFYVE9 NM_004799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.620

Genes affected

ZFYVE9 (HGNC:6775): (zinc finger FYVE-type containing 9) This gene encodes a double zinc finger motif-containing protein that participates in the transforming growth factor-beta (TGFB) signalling pathway. The encoded protein interacts directly with SMAD2 and SMAD3, and recruits SMAD2 to the TGFB receptor. There are multiple pseudogenes for this gene on chromosomes 2, 15, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

ZFYVE9 (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=0.06739938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE9	NM_004799.4	c.893G>C	p.Ser298Thr	missense_variant	4/19	ENST00000287727.8	NP_004790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE9	ENST00000287727.8	c.893G>C	p.Ser298Thr	missense_variant	4/19	5	NM_004799.4	ENSP00000287727.3
ZFYVE9	ENST00000371591.2	c.893G>C	p.Ser298Thr	missense_variant	5/20	1		ENSP00000360647.1
ZFYVE9	ENST00000357206.6	c.893G>C	p.Ser298Thr	missense_variant	4/18	1		ENSP00000349737.2
ZFYVE9	ENST00000361625.5	n.1065G>C		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Aug 09, 2021

The c.893G>C (p.S298T) alteration is located in exon 4 (coding exon 2) of the ZFYVE9 gene. This alteration results from a G to C substitution at nucleotide position 893, causing the serine (S) at amino acid position 298 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	Benign	0.061
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.8
DANN	Benign	0.82
DEOGEN2	Benign	0.0057	T;.;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.67	T;T;.
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.41	N;N;N
REVEL	Benign	0.048
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.57	T;T;T
Polyphen		0.020	B;B;B
Vest4		0.19
MVP		0.093
MPC		0.10
ClinPred		0.11	T
GERP RS		1.8
Varity_R		0.040
gMVP		0.14

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: rs1347247272; hg19: chr1-52703982;