rs554371710
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015346.4(ZFYVE26):c.3662T>A(p.Leu1221Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_015346.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250496Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135350
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461440Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11AN XY: 726958
GnomAD4 genome AF: 0.000144 AC: 22AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74490
ClinVar
Submissions by phenotype
Spastic paraplegia Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1221 of the ZFYVE26 protein (p.Leu1221Gln). This variant is present in population databases (rs554371710, gnomAD 0.009%). 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: 406176). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Inborn genetic diseases Uncertain:1
The c.3662T>A (p.L1221Q) alteration is located in exon 21 (coding exon 20) of the ZFYVE26 gene. This alteration results from a T to A substitution at nucleotide position 3662, causing the leucine (L) at amino acid position 1221 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at