14-67786135-A-T

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.3118T>A(p.Ser1040Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,614,158 control chromosomes in the GnomAD database, including 2,189 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 0.039 ( 204 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1985 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.344

Publications

16 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=0.0017139316).

BP6

Variant 14-67786135-A-T is Benign according to our data. Variant chr14-67786135-A-T is described in ClinVar as [Benign]. Clinvar id is 130778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.3118T>A	p.Ser1040Thr	missense_variant	Exon 17 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.3118T>A	p.Ser1040Thr	missense_variant	Exon 17 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5985

AN:

152172

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00934

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0306

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0497

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0494

AC:

12416

AN:

251448

AF XY:

0.0445

show subpopulations

Gnomad AFR exome

AF:

0.00849

Gnomad AMR exome

AF:

0.160

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0308

Gnomad NFE exome

AF:

0.0475

Gnomad OTH exome

AF:

0.0420

GnomAD4 exome

AF:

0.0458

AC:

66978

AN:

1461868

Hom.:

1985

Cov.:

AF XY:

0.0445

AC XY:

32382

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00726

AC:

243

AN:

33480

American (AMR)

AF:

0.152

AC:

6812

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

211

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0120

AC:

1038

AN:

86258

European-Finnish (FIN)

AF:

0.0344

AC:

1840

AN:

53418

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0489

AC:

54370

AN:

1111988

Other (OTH)

AF:

0.0396

AC:

2394

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3892

7783

11675

15566

19458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0393

AC:

5986

AN:

152290

Hom.:

204

Cov.:

AF XY:

0.0396

AC XY:

2952

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00931

AC:

387

AN:

41570

American (AMR)

AF:

0.112

AC:

1711

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0114

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0306

AC:

325

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0497

AC:

3379

AN:

68028

Other (OTH)

AF:

0.0441

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

294

589

883

1178

1472

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0451

Hom.:

166

Bravo

AF:

0.0435

TwinsUK

AF:

0.0485

AC:

180

ALSPAC

AF:

0.0441

AC:

170

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0420

AC:

361

ExAC

AF:

0.0444

AC:

5385

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0452

EpiControl

AF:

0.0404

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 08, 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. -

Jun 06, 2012

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 15

Benign:4

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2014

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

Oct 30, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.015

.;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.44

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.34

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.016

Sift

Benign

0.21

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.15

.;B

Vest4

0.31

MPC

0.17

ClinPred

0.0033

GERP RS

-0.57

gMVP

0.12

Mutation Taster

=97/3

polymorphism (auto)

(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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14-67786135-A-T

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