Genetic Variant ZFYVE21:p.Thr189Lys (chr14-103732659-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024071.4(ZFYVE21):c.566C>A(p.Thr189Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZFYVE21
NM_024071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Publications

1 publications found

Variant links:

Genes affected

ZFYVE21 (HGNC:20760): (zinc finger FYVE-type containing 21) Predicted to enable metal ion binding activity. Predicted to be located in endosome and focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ZFYVE21 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02869919).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024071.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE21	NM_024071.4	MANE Select	c.566C>A	p.Thr189Lys	missense	Exon 6 of 7	NP_076976.1	Q9BQ24-1
	ZFYVE21	NM_001198953.2		c.620C>A	p.Thr207Lys	missense	Exon 7 of 8	NP_001185882.1	Q9BQ24-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFYVE21	ENST00000311141.7	TSL:1 MANE Select	c.566C>A	p.Thr189Lys	missense	Exon 6 of 7	ENSP00000310543.2	Q9BQ24-1
ZFYVE21	ENST00000555501.1	TSL:1	n.3668C>A		non_coding_transcript_exon	Exon 5 of 6
ZFYVE21	ENST00000944811.1		c.779C>A	p.Thr260Lys	missense	Exon 8 of 9	ENSP00000614870.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000808

AC:

AN:

247406

AF XY:

0.00000747

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000598

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457972

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33196

American (AMR)

AF:

0.0000231

AC:

AN:

43340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25920

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110780

Other (OTH)

AF:

0.00

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.86

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0063

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.66

M_CAP

Benign

0.0074

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

PhyloP100

1.0

PrimateAI

Benign

0.30

PROVEAN

Benign

1.7

REVEL

Benign

0.075

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.29

MutPred

0.43

Gain of catalytic residue at G192 (P = 0.001)

MVP

0.043

MPC

0.44

ClinPred

0.034

GERP RS

-0.27

Varity_R

0.022

gMVP

0.31

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over