chr14-73211886-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM5PP2PP3_ModerateBS2_Supporting
The NM_000021.4(PSEN1):āc.1073G>Cā(p.Arg358Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000021.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.1073G>C | p.Arg358Pro | missense_variant | 10/12 | ENST00000324501.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSEN1 | ENST00000324501.10 | c.1073G>C | p.Arg358Pro | missense_variant | 10/12 | 1 | NM_000021.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251456Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461870Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727236
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151958Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 18, 2016 | - - |
Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2020 | 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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PSEN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 448142). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 358 of the PSEN1 protein (p.Arg358Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | PSEN1: PM5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at