chr14-67789467-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015346.4(ZFYVE26):c.2887G>C(p.Val963Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 1,614,220 control chromosomes in the GnomAD database, including 57 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0061 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0076 ( 50 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 2.75

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006394297).

BP6

Variant 14-67789467-C-G is Benign according to our data. Variant chr14-67789467-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188323.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00614 (936/152346) while in subpopulation AMR AF = 0.00824 (126/15298). AF 95% confidence interval is 0.00754. There are 7 homozygotes in GnomAd4. There are 446 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.2887G>C	p.Val963Leu	missense_variant	Exon 16 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.2887G>C	p.Val963Leu	missense_variant	Exon 16 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.00614

AC:

935

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00682

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00810

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00774

AC:

1943

AN:

251010

AF XY:

0.00783

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.0314

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00871

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00756

AC:

11052

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

5519

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

33480

American (AMR)

AF:

0.00854

AC:

382

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

816

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00588

AC:

507

AN:

86258

European-Finnish (FIN)

AF:

0.00303

AC:

162

AN:

53400

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00769

AC:

8549

AN:

1112012

Other (OTH)

AF:

0.00879

AC:

531

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

767

1534

2301

3068

3835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

320

640

960

1280

1600

<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:

0.00614

AC:

936

AN:

152346

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

446

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41578

American (AMR)

AF:

0.00824

AC:

126

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

100

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00703

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00810

AC:

551

AN:

68032

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00950

Hom.:

Bravo

AF:

0.00662

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.00761

AC:

924

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.0102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZFYVE26: BP4, BS2 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 01, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 28, 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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 15

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Spastic paraplegia

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Sep 09, 2021

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

0.23

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0084

.;T

Eigen

Benign

0.083

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-1.1

PhyloP100

2.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.040

Sift

Benign

0.25

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.32

.;B

Vest4

0.28

MVP

0.20

MPC

0.29

ClinPred

0.0049

GERP RS

4.7

gMVP

0.30

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over