chr1-52346131-G-T

Position:

• chr1-52346131-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004799.4(ZFYVE9):​c.4188G>T​(p.Leu1396Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.00

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE9	NM_004799.4	c.4188G>T	p.Leu1396Phe	missense_variant	19/19	ENST00000287727.8	NP_004790.2
ZFYVE9	NM_007324.5	c.4011G>T	p.Leu1337Phe	missense_variant	18/18		NP_015563.2
ZFYVE9	XM_011542437.3	c.4188G>T	p.Leu1396Phe	missense_variant	19/19		XP_011540739.1
ZFYVE9	XM_047434674.1	c.4011G>T	p.Leu1337Phe	missense_variant	18/18		XP_047290630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE9	ENST00000287727.8	c.4188G>T	p.Leu1396Phe	missense_variant	19/19	5	NM_004799.4	ENSP00000287727.3
ZFYVE9	ENST00000371591.2	c.4188G>T	p.Leu1396Phe	missense_variant	20/20	1		ENSP00000360647.1
ZFYVE9	ENST00000357206.6	c.4011G>T	p.Leu1337Phe	missense_variant	18/18	1		ENSP00000349737.2
CC2D1B	ENST00000470844.5	n.320C>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 22, 2022

The c.4188G>T (p.L1396F) alteration is located in exon 19 (coding exon 17) of the ZFYVE9 gene. This alteration results from a G to T substitution at nucleotide position 4188, causing the leucine (L) at amino acid position 1396 to be replaced by a phenylalanine (F). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.8	L;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.80
MutPred		0.33		Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);
MVP		0.79
MPC		1.8
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.78
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-52811803;