rs63750376
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000262410.10(MAPT):c.1991G>T(p.Gly664Val) variant causes a missense change involving the alteration of a 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. G664G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
MAPT
ENST00000262410.10 missense
ENST00000262410.10 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 9.78
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000262410.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941
PP5
Variant 17-45996657-G-T is Pathogenic according to our data. Variant chr17-45996657-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14246.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-45996657-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MAPT | NM_001377265.1 | c.1991G>T | p.Gly664Val | missense_variant | 9/13 | ENST00000262410.10 | NP_001364194.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MAPT | ENST00000262410.10 | c.1991G>T | p.Gly664Val | missense_variant | 9/13 | 1 | NM_001377265.1 | ENSP00000262410 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Frontotemporal dementia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 06, 2021 | - - |
not provided Other:1
not provided, no classification provided | literature only | VIB Department of Molecular Genetics, University of Antwerp | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;.;.;.;.;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;.;.;.;.;.;M;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D;D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;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 ubiquitination at K591 (P = 0.0598);.;.;.;.;.;.;.;.;Loss of ubiquitination at K591 (P = 0.0598);.;.;
MVP
MPC
2.3
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