rs1057518016
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015346.4(ZFYVE26):c.2254C>T(p.Gln752*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ZFYVE26
NM_015346.4 stop_gained
NM_015346.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.26
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-67797750-G-A is Pathogenic according to our data. Variant chr14-67797750-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZFYVE26 | NM_015346.4 | c.2254C>T | p.Gln752* | stop_gained | 12/42 | ENST00000347230.9 | NP_056161.2 | |
ZFYVE26 | XM_047431173.1 | c.2254C>T | p.Gln752* | stop_gained | 12/42 | XP_047287129.1 | ||
ZFYVE26 | XM_011536609.3 | c.2254C>T | p.Gln752* | stop_gained | 12/26 | XP_011534911.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZFYVE26 | ENST00000347230.9 | c.2254C>T | p.Gln752* | stop_gained | 12/42 | 1 | NM_015346.4 | ENSP00000251119.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251182Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135772
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727162
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 15 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with spastic paraplegia 15 (MIM#270700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in an individual with spastic paraplegia (PMID: 30555096) and classified as likely pathogenic and pathogenic in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 25, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 25, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 09, 2022 | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2024 | This sequence change creates a premature translational stop signal (p.Gln752*) in the ZFYVE26 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZFYVE26 are known to be pathogenic (PMID: 18394578, 19805727). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 24833714, 29858556, 30555096). ClinVar contains an entry for this variant (Variation ID: 372839). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2016 | The Q752X variant in the ZFYVE26 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q752X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q752X variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at