chr1-52346108-A-G

Position:

• chr1-52346108-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004799.4(ZFYVE9):​c.4165A>G​(p.Met1389Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,614 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZFYVE9 NM_004799.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.60

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]

CC2D1B (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08181739).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE9	NM_004799.4	c.4165A>G	p.Met1389Val	missense_variant	19/19	ENST00000287727.8	NP_004790.2
ZFYVE9	NM_007324.5	c.3988A>G	p.Met1330Val	missense_variant	18/18		NP_015563.2
ZFYVE9	XM_011542437.3	c.4165A>G	p.Met1389Val	missense_variant	19/19		XP_011540739.1
ZFYVE9	XM_047434674.1	c.3988A>G	p.Met1330Val	missense_variant	18/18		XP_047290630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE9	ENST00000287727.8	c.4165A>G	p.Met1389Val	missense_variant	19/19	5	NM_004799.4	ENSP00000287727.3
ZFYVE9	ENST00000371591.2	c.4165A>G	p.Met1389Val	missense_variant	20/20	1		ENSP00000360647.1
ZFYVE9	ENST00000357206.6	c.3988A>G	p.Met1330Val	missense_variant	18/18	1		ENSP00000349737.2
CC2D1B	ENST00000470844.5	n.343T>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460614 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726464

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 29, 2024

The c.4165A>G (p.M1389V) alteration is located in exon 19 (coding exon 17) of the ZFYVE9 gene. This alteration results from a A to G substitution at nucleotide position 4165, causing the methionine (M) at amino acid position 1389 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	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.090	T;.;T
Eigen	Benign	-0.048
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;.
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D;N;D
REVEL	Benign	0.066
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.082	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.31
MutPred		0.16		Loss of disorder (P = 0.1023);.;Loss of disorder (P = 0.1023);
MVP		0.19
MPC		0.69
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.47
gMVP		0.50

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: rs537232506; hg19: chr1-52811780;