chr14-73024027-T-C

Position:

• chr14-73024027-T-C

Variant summary

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

The NM_021260.4(ZFYVE1):​c.482A>G​(p.Gln161Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZFYVE1 NM_021260.4 missense, splice_region
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

Genes affected

ZFYVE1 (HGNC:13180): (zinc finger FYVE-type containing 1) The FYVE domain mediates the recruitment of proteins involved in membrane trafficking and cell signaling to phosphatidylinositol 3-phosphate-containing membranes. This protein contains two zinc-binding FYVE domains in tandem and is reported to localize to the Golgi apparatus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFYVE1	NM_021260.4	c.482A>G	p.Gln161Arg	missense_variant, splice_region_variant	2/12	ENST00000556143.6	NP_067083.1
ZFYVE1	NM_001281734.2	c.482A>G	p.Gln161Arg	missense_variant, splice_region_variant	2/12		NP_001268663.1
ZFYVE1	XM_047431481.1	c.482A>G	p.Gln161Arg	missense_variant, splice_region_variant	2/7		XP_047287437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFYVE1	ENST00000556143.6	c.482A>G	p.Gln161Arg	missense_variant, splice_region_variant	2/12	1	NM_021260.4	ENSP00000450742.1
ZFYVE1	ENST00000318876.9	c.482A>G	p.Gln161Arg	missense_variant, splice_region_variant	2/12	1		ENSP00000326921.5
ZFYVE1	ENST00000553891.5	c.482A>G	p.Gln161Arg	missense_variant, splice_region_variant	2/13	5		ENSP00000452442.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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 27, 2022

The c.482A>G (p.Q161R) alteration is located in exon 2 (coding exon 1) of the ZFYVE1 gene. This alteration results from a A to G substitution at nucleotide position 482, causing the glutamine (Q) at amino acid position 161 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	0.13
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	.;M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.22	B;.;P
Vest4		0.76
MutPred		0.26		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.39
MPC		0.33
ClinPred		0.61	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.060		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: chr14-73490735;