chr17-46010324-TAAG-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM4_SupportingPP3PP5
The NM_001377265.1(MAPT):c.2017_2019delAAG(p.Lys673del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,421,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001377265.1 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAPT | NM_001377265.1 | c.2017_2019delAAG | p.Lys673del | conservative_inframe_deletion | Exon 10 of 13 | ENST00000262410.10 | NP_001364194.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAPT | ENST00000262410.10 | c.2017_2019delAAG | p.Lys673del | conservative_inframe_deletion | Exon 10 of 13 | 1 | NM_001377265.1 | ENSP00000262410.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000262 AC: 5AN: 190682Hom.: 0 AF XY: 0.0000296 AC XY: 3AN XY: 101220
GnomAD4 exome AF: 0.0000148 AC: 21AN: 1421888Hom.: 0 AF XY: 0.0000142 AC XY: 10AN XY: 703118
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Frontotemporal dementia Pathogenic:1Uncertain:1
- -
This variant, c.841_843del, results in the deletion of 1 amino acid(s) of the MAPT protein (p.Lys281del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755349386, gnomAD 0.01%). This variant has been observed in individual(s) with frontotemporal dementia and Alzheimer's disease (PMID: 9973279, 10514099, 17723255). This variant is also known as p.Lys280del and ΔK280. ClinVar contains an entry for this variant (Variation ID: 98213). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MAPT function (PMID: 9973279, 18725924, 23515417, 24448233). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
not provided Pathogenic:1Other:1
- -
Previously reported in individuals with frontotemporal dementia and Alzheimer disease; however segregation information was not available (PMID: 17723255, 32843152, 9973279); Published functional studies have demonstrated reduced ability to promote microtubule assembly compared to wild type protein, as well as altered protein conformation resulting in increased propensity to form tau aggregates (PMID: 24453187, 9973279, 11102510); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19498037, 11756436, 11102510, 23515417, 18725924, 9973279, 24448233, 32843152, 32741062, 10514099, 37351604, 24453187, 17723255) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at