rs768176054
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015346.4(ZFYVE26):c.2450del(p.Leu817CysfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L817L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015346.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZFYVE26 | NM_015346.4 | c.2450del | p.Leu817CysfsTer12 | frameshift_variant | 14/42 | ENST00000347230.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZFYVE26 | ENST00000347230.9 | c.2450del | p.Leu817CysfsTer12 | frameshift_variant | 14/42 | 1 | NM_015346.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152030Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251146Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135754
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24AN XY: 727176
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152030Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74248
ClinVar
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change creates a premature translational stop signal (p.Leu817Cysfs*12) 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 (rs768176054, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with a ZFYVE26-related condition (PMID: 25497598). ClinVar contains an entry for this variant (Variation ID: 430412). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2017 | The c.2450delT variant in the ZFYVE26 gene has been previously reported in the heterozygous state in the presence of a second ZFYVE26 variant in an individual with cerebellar ataxia, axonal sensorimotor neuropathy, and generalized atrophy on brain MRI (Pyle et al., 2015). The c.2450delT variant causes a frameshift starting with codon Leucine 817, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Leu817CysfsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2450delT variant is not observed in the homozygous state, or at a significant frequency, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2450delT as a pathogenic variant. - |
Hereditary spastic paraplegia 15 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 15, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at