rs3742884

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015346.4(ZFYVE26):c.3365C>T(p.Ala1122Val) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,613,908 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 315 hom., cov: 32)

Exomes 𝑓: 0.019 ( 529 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.67

Publications

14 publications found

Variant links:

Genes affected

ZFYVE26 (HGNC:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

ZFYVE26 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 15
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, G2P

ZFYVE26 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001244396).

BP6

Variant 14-67785217-G-A is Benign according to our data. Variant chr14-67785217-G-A is described in ClinVar as Benign. ClinVar VariationId is 130781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.3365C>T	p.Ala1122Val	missense_variant	Exon 19 of 42	ENST00000347230.9	NP_056161.2	Q68DK2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 link	c.3365C>T	p.Ala1122Val	missense_variant	Exon 19 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.0454

AC:

6914

AN:

152146

Hom.:

315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0515

Gnomad SAS

AF:

0.0195

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.0421

GnomAD2 exomes

AF:

0.0246

AC:

6152

AN:

249942

AF XY:

0.0228

show subpopulations

Gnomad AFR exome

AF:

0.127

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.0516

Gnomad FIN exome

AF:

0.00806

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0195

AC:

28484

AN:

1461644

Hom.:

529

Cov.:

AF XY:

0.0192

AC XY:

13992

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.119

AC:

3996

AN:

33468

American (AMR)

AF:

0.0114

AC:

509

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

299

AN:

26134

East Asian (EAS)

AF:

0.0602

AC:

2389

AN:

39698

South Asian (SAS)

AF:

0.0194

AC:

1670

AN:

86250

European-Finnish (FIN)

AF:

0.00929

AC:

496

AN:

53396

Middle Eastern (MID)

AF:

0.0368

AC:

212

AN:

5768

European-Non Finnish (NFE)

AF:

0.0157

AC:

17475

AN:

1111858

Other (OTH)

AF:

0.0238

AC:

1438

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

1614

3229

4843

6458

8072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

754

1508

2262

3016

3770

<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

AF:

0.0455

AC:

6927

AN:

152264

Hom.:

315

Cov.:

AF XY:

0.0440

AC XY:

3275

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.121

AC:

5008

AN:

41534

American (AMR)

AF:

0.0195

AC:

298

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0519

AC:

268

AN:

5168

South Asian (SAS)

AF:

0.0197

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00885

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1024

AN:

68032

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

315

630

946

1261

1576

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0260

Hom.:

520

Bravo

AF:

0.0506

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.122

AC:

538

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0275

AC:

3339

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

EpiCase

AF:

0.0159

EpiControl

AF:

0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 25, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Sep 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hereditary spastic paraplegia 15

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.0089

.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.71

.;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.99

PhyloP100

3.7

PrimateAI

Benign

0.37

PROVEAN

Benign

0.39

N;N

REVEL

Benign

0.088

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.012

.;B

Vest4

0.083

MPC

0.17

ClinPred

0.0085

GERP RS

2.7

gMVP

0.087

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over