chr14-67786228-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_015346.4(ZFYVE26):​c.3025C>T​(p.Arg1009Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,293,332 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1009Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000065 ( 0 hom., cov: 30)
Exomes 𝑓: 0.00015 ( 4 hom. )

Consequence

ZFYVE26
NM_015346.4 missense

Scores

2
1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

Publications

1 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.026570886).
BS1
Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00015 (175/1170360) while in subpopulation SAS AF = 0.00176 (135/76712). AF 95% confidence interval is 0.00152. There are 4 homozygotes in GnomAdExome4. There are 130 alleles in the male GnomAdExome4 subpopulation. Median coverage is 40. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZFYVE26NM_015346.4 linkc.3025C>T p.Arg1009Trp 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
ZFYVE26ENST00000347230.9 linkc.3025C>T p.Arg1009Trp missense_variant Exon 17 of 42 1 NM_015346.4 ENSP00000251119.5 Q68DK2-1

Frequencies

GnomAD3 genomes
AF:
0.0000651
AC:
8
AN:
122892
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000296
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00134
Gnomad FIN
AF:
0.000225
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000160
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000269
AC:
63
AN:
234122
AF XY:
0.000370
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000951
Gnomad NFE exome
AF:
0.0000279
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000150
AC:
175
AN:
1170360
Hom.:
4
Cov.:
40
AF XY:
0.000222
AC XY:
130
AN XY:
585412
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
27068
American (AMR)
AF:
0.00
AC:
0
AN:
39104
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21594
East Asian (EAS)
AF:
0.00
AC:
0
AN:
21056
South Asian (SAS)
AF:
0.00176
AC:
135
AN:
76712
European-Finnish (FIN)
AF:
0.000155
AC:
7
AN:
45166
Middle Eastern (MID)
AF:
0.000224
AC:
1
AN:
4472
European-Non Finnish (NFE)
AF:
0.0000281
AC:
25
AN:
888524
Other (OTH)
AF:
0.000150
AC:
7
AN:
46664
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.456
Heterozygous variant carriers
0
8
17
25
34
42
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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:
0.0000651
AC:
8
AN:
122972
Hom.:
0
Cov.:
30
AF XY:
0.0000707
AC XY:
4
AN XY:
56610
show subpopulations
African (AFR)
AF:
0.0000295
AC:
1
AN:
33862
American (AMR)
AF:
0.00
AC:
0
AN:
8972
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3324
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3526
South Asian (SAS)
AF:
0.00134
AC:
5
AN:
3740
European-Finnish (FIN)
AF:
0.000225
AC:
1
AN:
4448
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
182
European-Non Finnish (NFE)
AF:
0.0000160
AC:
1
AN:
62376
Other (OTH)
AF:
0.00
AC:
0
AN:
1682
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.444
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000329
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.000264
AC:
32
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spastic paraplegia Uncertain:1
Sep 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1009 of the ZFYVE26 protein (p.Arg1009Trp). This variant is present in population databases (rs374605354, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. 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: 527991). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.36
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.068
.;T
Eigen
Benign
-0.012
Eigen_PC
Benign
-0.084
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.84
.;T
M_CAP
Benign
0.079
D
MetaRNN
Benign
0.027
T;T
MetaSVM
Benign
-0.74
T
PhyloP100
2.2
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.20
Sift
Uncertain
0.0030
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
.;D
Vest4
0.53
MutPred
0.44
Loss of disorder (P = 0.0089);Loss of disorder (P = 0.0089);
MVP
0.48
MPC
0.63
ClinPred
0.23
T
GERP RS
2.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.29
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs374605354; hg19: chr14-68252945; API