rs3742885

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3308C>T(p.Pro1103Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,597,948 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1103H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.048 ( 345 hom., cov: 32)

Exomes 𝑓: 0.022 ( 834 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.43

Publications

13 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=0.0013165772).

BP6

Variant 14-67785274-G-A is Benign according to our data. Variant chr14-67785274-G-A is described in ClinVar as Benign. ClinVar VariationId is 130780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.3308C>T	p.Pro1103Leu	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.3308C>T	p.Pro1103Leu	missense_variant	Exon 19 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.0484

AC:

7357

AN:

152136

Hom.:

345

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0195

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0224

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0468

GnomAD2 exomes

AF:

0.0307

AC:

6698

AN:

218408

AF XY:

0.0285

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.00827

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

AF:

0.0218

AC:

31453

AN:

1445694

Hom.:

834

Cov.:

AF XY:

0.0215

AC XY:

15454

AN XY:

717982

show subpopulations

African (AFR)

AF:

0.119

AC:

3933

AN:

32992

American (AMR)

AF:

0.0121

AC:

492

AN:

40768

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

338

AN:

25860

East Asian (EAS)

AF:

0.132

AC:

5117

AN:

38882

South Asian (SAS)

AF:

0.0207

AC:

1754

AN:

84888

European-Finnish (FIN)

AF:

0.00934

AC:

493

AN:

52796

Middle Eastern (MID)

AF:

0.0379

AC:

207

AN:

5466

European-Non Finnish (NFE)

AF:

0.0158

AC:

17443

AN:

1104170

Other (OTH)

AF:

0.0280

AC:

1676

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

1498

2997

4495

5994

7492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

784

1568

2352

3136

3920

<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:

0.0484

AC:

7370

AN:

152254

Hom.:

345

Cov.:

AF XY:

0.0473

AC XY:

3518

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.121

AC:

5017

AN:

41532

American (AMR)

AF:

0.0195

AC:

298

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3472

East Asian (EAS)

AF:

0.127

AC:

656

AN:

5170

South Asian (SAS)

AF:

0.0226

AC:

109

AN:

4820

European-Finnish (FIN)

AF:

0.00904

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0153

AC:

1038

AN:

68020

Other (OTH)

AF:

0.0468

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

341

681

1022

1362

1703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0248

Hom.:

481

Bravo

AF:

0.0539

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.120

AC:

529

ESP6500EA

AF:

0.0157

AC:

135

ExAC

AF:

0.0303

AC:

3636

Asia WGS

AF:

0.0690

AC:

241

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

Aug 02, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 15

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

0.092

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0078

.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

.;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.1

PhyloP100

2.4

PrimateAI

Benign

0.36

PROVEAN

Benign

0.11

N;N

REVEL

Benign

0.065

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.47

.;P

Vest4

0.084

MPC

0.17

ClinPred

0.013

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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