rs146968463

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

1
17

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]

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
ZFYVE26NM_015346.4 linkc.5260G>A p.Ala1754Thr missense_variant Exon 27 of 42 ENST00000347230.9 NP_056161.2 Q68DK2-1
ZFYVE26XM_047431173.1 linkc.5260G>A p.Ala1754Thr missense_variant Exon 27 of 42 XP_047287129.1
ZFYVE26XM_047431174.1 linkc.2935G>A p.Ala979Thr missense_variant Exon 16 of 31 XP_047287130.1
ZFYVE26XM_047431175.1 linkc.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
ZFYVE26ENST00000347230.9 linkc.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:
64
AN:
152114
Hom.:
0
Cov.:
32
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:
93
AN:
248244
Hom.:
0
AF XY:
0.000403
AC XY:
54
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.:
1
Cov.:
31
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:
64
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.000430
AC XY:
32
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.:
0
Bravo
AF:
0.000416
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.000231
AC:
28

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
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 29, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jan 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary spastic paraplegia 15 Uncertain:4
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 25, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

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. -

Sep 06, 2019
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:2
Feb 01, 2017
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 26, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Spastic paraplegia Uncertain:1
Sep 19, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 11, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Nov 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0054
.;T
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.74
.;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.020
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.34
T
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
T
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.

Other links and lift over

dbSNP: rs146968463; hg19: chr14-68241793; COSMIC: COSV61332273; COSMIC: COSV61332273; API