17-46024061-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_001377265.1(MAPT):c.2392C>T(p.Arg798Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
MAPT
NM_001377265.1 missense
NM_001377265.1 missense
Scores
3
9
7
Clinical Significance
Conservation
PhyloP100: 2.20
Genes affected
MAPT (HGNC:6893): (microtubule associated protein tau) This gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex, regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system, depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PP5
Variant 17-46024061-C-T is Pathogenic according to our data. Variant chr17-46024061-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46024061-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.2905081). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAPT | NM_001377265.1 | c.2392C>T | p.Arg798Trp | missense_variant | 13/13 | ENST00000262410.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAPT | ENST00000262410.10 | c.2392C>T | p.Arg798Trp | missense_variant | 13/13 | 1 | NM_001377265.1 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251284Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727220
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5Other:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2021 | Published functional studies demonstrate that R406W cells show a decreased level of phosphorylation and are unable to bind to microtubules resulting in accumulation in the cytoplasm (Perez et al., 2000; Delobel et al., 2002).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33061333, 30924900, 30562452, 31836585, 31127772, 29370822, 30279455, 23727082, 20683187, 18587238, 10514099, 14517953, 9641683, 18284428, 11889249, 12368474, 11278002, 29253099, 25942996, 26734663, 25377499, 26028272, 26581847, 20377816, 22787795, 21849646, 18992292, 11102510, 21339331, 23105105, 19304664, 11756436, 23338682, 20634584, 24150109, 10820221, 18803694, 22368988, 23383383) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 26, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Frontotemporal dementia Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 12, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 01, 2023 | This missense change has been observed in individuals with behavioral variant frontotemporal dementia (bvFTD), Alzheimer's disease, and/or mixed dementia with parkinsonism (PMID: 9382467, 9641683, 11117542, 11889249, 23383383, 23727082, 25942996, 26028272). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63750424, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the MAPT protein (p.Arg406Trp). ClinVar contains an entry for this variant (Variation ID: 14247). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MAPT function (PMID: 10797541, 11102510, 11756436, 19304664, 21339331, 24150109). 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 MAPT protein function. - |
Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 15, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;.;.;.;.;.;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;.;.;.;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.;.;.;.;.;L;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D;.;.;D;D;.;.;.
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;.;.;D;D;.;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;.;D;D;D;D;D;D;D;.
Vest4
MutPred
Loss of disorder (P = 0.0292);.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0292);.;.;
MVP
MPC
2.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at