rs764479245
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5
The NM_015346.4(ZFYVE26):c.6744_6746del(p.Lys2248del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
ZFYVE26
NM_015346.4 inframe_deletion
NM_015346.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.22
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
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Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_015346.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
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Variant 14-67755987-GTTC-G is Pathogenic according to our data. Variant chr14-67755987-GTTC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241056.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZFYVE26 | NM_015346.4 | c.6744_6746del | p.Lys2248del | inframe_deletion | 36/42 | ENST00000347230.9 | |
ZFYVE26 | XM_047431173.1 | c.6744_6746del | p.Lys2248del | inframe_deletion | 36/42 | ||
ZFYVE26 | XM_047431174.1 | c.4419_4421del | p.Lys1473del | inframe_deletion | 25/31 | ||
ZFYVE26 | XM_047431175.1 | c.4326_4328del | p.Lys1442del | inframe_deletion | 25/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZFYVE26 | ENST00000347230.9 | c.6744_6746del | p.Lys2248del | inframe_deletion | 36/42 | 1 | NM_015346.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251448Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135888
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461892Hom.: 0 AF XY: 0.0000165 AC XY: 12AN XY: 727246
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152348Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2024 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36315648, 24833714, 37681008) - |
Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2022 | This variant, c.6744_6746del, results in the deletion of 1 amino acid(s) of the ZFYVE26 protein (p.Lys2248del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs764479245, gnomAD 0.007%). This variant has been observed in individual(s) with complicated spastic paraplegia (PMID: 24833714). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 241056). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Hereditary spastic paraplegia 15 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 25, 2018 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at