rs146968463

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015346.4(ZFYVE26):c.5260G>A(p.Ala1754Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,612,254 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 1 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11B:3

Conservation

PhyloP100: 0.774

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019519866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFYVE26	NM_015346.4 link	c.5260G>A	p.Ala1754Thr	missense_variant	Exon 27 of 42	ENST00000347230.9	NP_056161.2	Q68DK2-1
ZFYVE26	XM_047431173.1 link	c.5260G>A	p.Ala1754Thr	missense_variant	Exon 27 of 42		XP_047287129.1
ZFYVE26	XM_047431174.1 link	c.2935G>A	p.Ala979Thr	missense_variant	Exon 16 of 31		XP_047287130.1
ZFYVE26	XM_047431175.1 link	c.2842G>A	p.Ala948Thr	missense_variant	Exon 16 of 31		XP_047287131.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFYVE26	ENST00000347230.9 link	c.5260G>A	p.Ala1754Thr	missense_variant	Exon 27 of 42	1	NM_015346.4	ENSP00000251119.5		Q68DK2-1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000375

AC:

AN:

248244

Hom.:

AF XY:

0.000403

AC XY:

AN XY:

133966

show subpopulations

Gnomad AFR exome

AF:

0.000561

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.000720

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000783

AC:

1143

AN:

1460022

Hom.:

Cov.:

AF XY:

0.000788

AC XY:

572

AN XY:

726128

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.000994

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000420

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000663

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26740555, 28719003) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary spastic paraplegia 15

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	A heterozygous missense variant was identified, NM_015346.3(ZFYVE26):c.5260G>A in exon 27 of 42 of the ZFYVE26 gene. This substitution is predicted to create a moderate amino acid change from an alanine to a threonine at position 1754 of the protein; NP_056161.2(ZFYVE26):p.(Ala1754Thr). The alanine at this position has low conservation (100 vertebrates, UCSC), and is located within the retinal superfamily domain (NCBI). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.04% (104 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.07%. This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2024	Variant summary: ZFYVE26 c.5260G>A (p.Ala1754Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 248244 control chromosomes. This frequency does not allow conclusion about variant significance. To our knowledge, no occurrence of c.5260G>A in individuals affected with Hereditary Spastic Paraplegia 15 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 219623). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 01, 2017	- -

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1754 of the ZFYVE26 protein (p.Ala1754Thr). This variant is present in population databases (rs146968463, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ZFYVE26-related conditions. ClinVar contains an entry for this variant (Variation ID: 219623). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.5260G>A (p.A1754T) alteration is located in exon 27 (coding exon 26) of the ZFYVE26 gene. This alteration results from a G to A substitution at nucleotide position 5260, causing the alanine (A) at amino acid position 1754 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0054

.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.74

.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.33

N;N

REVEL

Benign

0.018

Sift

Benign

0.55

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.10

.;B

Vest4

0.18

MVP

0.072

MPC

0.16

ClinPred

0.025

GERP RS

4.9

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over