rs752283089
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000347230.9(ZFYVE26):c.3935C>A(p.Ser1312Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
ZFYVE26
ENST00000347230.9 stop_gained
ENST00000347230.9 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.26
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 14-67783217-G-T is Pathogenic according to our data. Variant chr14-67783217-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 225014.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.3935C>A | p.Ser1312Ter | stop_gained | 21/42 | ENST00000347230.9 | NP_056161.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZFYVE26 | ENST00000347230.9 | c.3935C>A | p.Ser1312Ter | stop_gained | 21/42 | 1 | NM_015346.4 | ENSP00000251119 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251008Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135634
GnomAD3 exomes
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251008
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135634
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GnomAD4 exome Cov.: 34
GnomAD4 exome
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34
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ExAC
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1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 03, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225014). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 24030950, 24833714). This variant is present in population databases (rs752283089, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser1312*) 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). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 07, 2014 | The c.3935C>A (p.S1312*) alteration, located in exon 21 (coding exon 20) of the ZFYVE26 gene, consists of a C to A substitution at nucleotide position 3935. This changes the amino acid from a serine (S) to a stop codon at amino acid position 1312. Premature stop codons are typically deleterious in nature (Richards, 2015). Based on data from the NHLBI Exome Sequencing Project (ESP), the c.3935C>A alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES: Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
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