rs146968463
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_015346.4(ZFYVE26):c.5260G>A(p.Ala1754Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,612,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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 Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ZFYVE26 | NM_015346.4 | c.5260G>A | p.Ala1754Thr | missense_variant | 27/42 | ENST00000347230.9 | |
ZFYVE26 | XM_047431173.1 | c.5260G>A | p.Ala1754Thr | missense_variant | 27/42 | ||
ZFYVE26 | XM_047431174.1 | c.2935G>A | p.Ala979Thr | missense_variant | 16/31 | ||
ZFYVE26 | XM_047431175.1 | c.2842G>A | p.Ala948Thr | missense_variant | 16/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ZFYVE26 | ENST00000347230.9 | c.5260G>A | p.Ala1754Thr | missense_variant | 27/42 | 1 | NM_015346.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000421 AC: 64AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000375 AC: 93AN: 248244Hom.: 0 AF XY: 0.000403 AC XY: 54AN XY: 133966
GnomAD4 exome AF: 0.000783 AC: 1143AN: 1460022Hom.: 1 Cov.: 31 AF XY: 0.000788 AC XY: 572AN XY: 726128
GnomAD4 genome ? AF: 0.000420 AC: 64AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32AN XY: 74428
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary spastic paraplegia 15 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 25, 2020 | A heterozygous missense variant was identified, NM_015346.3(ZFYVE26):c.5260G>A in exon 27 of 42 of the ZFYVE26 gene. This substitution is predicted to create a moderate amino acid change from an alanine to a threonine at position 1754 of the protein; NP_056161.2(ZFYVE26):p.(Ala1754Thr). The alanine at this position has low conservation (100 vertebrates, UCSC), and is located within the retinal superfamily domain (NCBI). In silico software predicts this variant to be tolerated (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.04% (104 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.07%. This variant has not previously been reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VUS with LOW CLINICAL RELEVANCE. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Sep 06, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 26, 2024 | Variant summary: ZFYVE26 c.5260G>A (p.Ala1754Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 248244 control chromosomes. This frequency does not allow conclusion about variant significance. To our knowledge, no occurrence of c.5260G>A in individuals affected with Hereditary Spastic Paraplegia 15 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 219623). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1754 of the ZFYVE26 protein (p.Ala1754Thr). This variant is present in population databases (rs146968463, gnomAD 0.07%). 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: 219623). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The c.5260G>A (p.A1754T) alteration is located in exon 27 (coding exon 26) of the ZFYVE26 gene. This alteration results from a G to A substitution at nucleotide position 5260, causing the alanine (A) at amino acid position 1754 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at