rs199745141
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_014855.3(AP5Z1):c.2221G>A(p.Glu741Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000272 in 1,612,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E741Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_014855.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.2221G>A | p.Glu741Lys | missense_variant | 17/17 | ENST00000649063.2 | |
AP5Z1 | NM_001364858.1 | c.1753G>A | p.Glu585Lys | missense_variant | 16/16 | ||
AP5Z1 | XM_047421098.1 | c.1885G>A | p.Glu629Lys | missense_variant | 15/15 | ||
AP5Z1 | NR_157345.1 | n.2352G>A | non_coding_transcript_exon_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP5Z1 | ENST00000649063.2 | c.2221G>A | p.Glu741Lys | missense_variant | 17/17 | NM_014855.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000976 AC: 24AN: 245996Hom.: 0 AF XY: 0.000119 AC XY: 16AN XY: 134022
GnomAD4 exome AF: 0.000292 AC: 427AN: 1459976Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 223AN XY: 726238
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74516
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 48 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 25, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 741 of the AP5Z1 protein (p.Glu741Lys). This variant is present in population databases (rs199745141, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with AP5Z1-related conditions. ClinVar contains an entry for this variant (Variation ID: 471497). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AP5Z1 protein function with a negative predictive value of 80%. 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 | Sep 14, 2022 | The c.2221G>A (p.E741K) alteration is located in exon 17 (coding exon 17) of the AP5Z1 gene. This alteration results from a G to A substitution at nucleotide position 2221, causing the glutamic acid (E) at amino acid position 741 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 03, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at