Genetic Variant ZFYVE21:p.His27Gln (chr14-103715922-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024071.4(ZFYVE21):c.81C>A(p.His27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZFYVE21
NM_024071.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.808

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22195667).

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.81C>A	p.His27Gln	missense	Exon 1 of 7	NP_076976.1	Q9BQ24-1
	ZFYVE21	NM_001198953.2		c.81C>A	p.His27Gln	missense	Exon 1 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.81C>A	p.His27Gln	missense	Exon 1 of 7	ENSP00000310543.2	Q9BQ24-1
ZFYVE21	ENST00000944811.1		c.81C>A	p.His27Gln	missense	Exon 1 of 9	ENSP00000614870.1
ZFYVE21	ENST00000892139.1		c.81C>A	p.His27Gln	missense	Exon 1 of 8	ENSP00000562198.1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1282988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

633630

African (AFR)

AF:

0.00

AC:

AN:

25754

American (AMR)

AF:

0.00

AC:

AN:

25126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21728

East Asian (EAS)

AF:

0.00

AC:

AN:

26052

South Asian (SAS)

AF:

0.00

AC:

AN:

70366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3920

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1017812

Other (OTH)

AF:

0.00

AC:

AN:

51178

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151262

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67686

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.016

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

PhyloP100

0.81

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.3

REVEL

Benign

0.023

Sift

Benign

0.050

Sift4G

Uncertain

0.033

Polyphen

0.48

Vest4

0.20

MutPred

0.29

Gain of catalytic residue at E26 (P = 0.0984)

MVP

0.16

MPC

0.49

ClinPred

0.43

GERP RS

2.5

PromoterAI

-0.0058

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.24

Mutation Taster

=69/31

polymorphism

(source)

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

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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