chr14-73170813-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBP6BS2
The NM_000021.4(PSEN1):c.104G>A(p.Arg35Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00038 in 1,614,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000021.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PSEN1 | NM_000021.4 | c.104G>A | p.Arg35Gln | missense_variant | Exon 4 of 12 | ENST00000324501.10 | NP_000012.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000289 AC: 44AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000179 AC: 45AN: 251364Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135876
GnomAD4 exome AF: 0.000390 AC: 570AN: 1461818Hom.: 1 Cov.: 32 AF XY: 0.000371 AC XY: 270AN XY: 727214
GnomAD4 genome AF: 0.000289 AC: 44AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23AN XY: 74450
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Variant summary: PSEN1 c.104G>A (p.Arg35Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PSEN1 causing Alzheimer Disease, Type 3, allowing no conclusion about variant significance. c.104G>A has been reported in the literature in individuals affected with Alzheimer Disease, Type 3 without strong evidence for causality and non-segregation has been reported in one family (e.g. Rogaeva_2001, Raux_2005, Guerreiro_2010, Rehker_2017). Experimental evidence evaluating an impact on protein function showed moderate to no effect of this variant on amyloid beta 42/40 pepitide ratios in vitro compared to the WT protein (e.g. Sun_2017, Hsu_2020, Petit_2022). The following publications have been ascertained in the context of this evaluation (PMID: 18667258, 32087291, 35365805, 28985224, 11524469, 27930341). ClinVar contains an entry for this variant (Variation ID: 98004). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
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not provided Benign:1Other:1
This variant is associated with the following publications: (PMID: 28554858, 16923167, 26159191, 32087291, 30924900, 27930341, 11524469, 23990795, 18667258, 23861362) -
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Alzheimer disease 3 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Alzheimer disease Uncertain:1
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Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Benign:1
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Dilated cardiomyopathy 1U Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at