rs7143196

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015346.4(ZFYVE26):c.2559G>A(p.Leu853Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,613,194 control chromosomes in the GnomAD database, including 30,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L853L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 1964 hom., cov: 32)

Exomes 𝑓: 0.19 ( 28537 hom. )

Consequence

ZFYVE26
NM_015346.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0140

Publications

17 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 14-67790768-C-T is Benign according to our data. Variant chr14-67790768-C-T is described in ClinVar as Benign. ClinVar VariationId is 130777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.014 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.2559G>A	p.Leu853Leu	synonymous_variant	Exon 15 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.2559G>A	p.Leu853Leu	synonymous_variant	Exon 15 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21131

AN:

152092

Hom.:

1965

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.195

Gnomad EAS

AF:

0.0167

Gnomad SAS

AF:

0.0644

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.125

GnomAD2 exomes

AF:

0.145

AC:

36452

AN:

251408

AF XY:

0.147

show subpopulations

Gnomad AFR exome

AF:

0.0363

Gnomad AMR exome

AF:

0.0960

Gnomad ASJ exome

AF:

0.193

Gnomad EAS exome

AF:

0.0176

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.160

GnomAD4 exome

AF:

0.189

AC:

276408

AN:

1460984

Hom.:

28537

Cov.:

AF XY:

0.186

AC XY:

135534

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.0323

AC:

1080

AN:

33470

American (AMR)

AF:

0.0976

AC:

4367

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

4915

AN:

26120

East Asian (EAS)

AF:

0.0218

AC:

867

AN:

39686

South Asian (SAS)

AF:

0.0750

AC:

6469

AN:

86198

European-Finnish (FIN)

AF:

0.187

AC:

9985

AN:

53398

Middle Eastern (MID)

AF:

0.110

AC:

637

AN:

5766

European-Non Finnish (NFE)

AF:

0.214

AC:

237787

AN:

1111256

Other (OTH)

AF:

0.171

AC:

10301

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

11464

22927

34391

45854

57318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8034

16068

24102

32136

40170

<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:

0.139

AC:

21130

AN:

152210

Hom.:

1964

Cov.:

AF XY:

0.134

AC XY:

9955

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0428

AC:

1777

AN:

41546

American (AMR)

AF:

0.101

AC:

1538

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.195

AC:

677

AN:

3470

East Asian (EAS)

AF:

0.0168

AC:

AN:

5184

South Asian (SAS)

AF:

0.0655

AC:

316

AN:

4828

European-Finnish (FIN)

AF:

0.181

AC:

1916

AN:

10580

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14377

AN:

67994

Other (OTH)

AF:

0.124

AC:

261

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

902

1804

2706

3608

4510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.183

Hom.:

5452

Bravo

AF:

0.128

Asia WGS

AF:

0.0450

AC:

157

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.194

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 15, 2017

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. -

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. -

Jul 24, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 15

Benign:2

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. -

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

- -

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.1

(source)

DANN

Benign

0.75

PhyloP100

-0.014

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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