rs63750756
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001377265.1(MAPT):c.2013T>G(p.Asn671Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
MAPT
NM_001377265.1 missense
NM_001377265.1 missense
Scores
4
13
2
Clinical Significance
Conservation
PhyloP100: 3.03
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 Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.802
PP5
?
Variant 17-46010324-T-G is Pathogenic according to our data. Variant chr17-46010324-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 14253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46010324-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAPT | NM_001377265.1 | c.2013T>G | p.Asn671Lys | missense_variant | 10/13 | ENST00000262410.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAPT | ENST00000262410.10 | c.2013T>G | p.Asn671Lys | missense_variant | 10/13 | 1 | NM_001377265.1 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MAPT: PP1:Strong, PS1, PM2, PS3:Moderate, PS4:Moderate - |
not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 19, 2021 | - - |
Frontotemporal dementia Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 279 of the MAPT protein (p.Asn279Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with frontotemporal dementia (PMID: 9789048, 10412802, 10489057, 10802785, 14568818, 22818528, 26295349, 27082848). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14253). 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 expected to disrupt MAPT protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551862:Progressive supranuclear ophthalmoplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;.;.;.;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.;.;.;L;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;.;D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;.;D;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;P;D;D;P;D;D;D;P
Vest4
MutPred
Gain of catalytic residue at N596 (P = 0.0171);.;.;.;.;.;.;Gain of catalytic residue at N596 (P = 0.0171);.;
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at