rs63750376

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

Scores

13
5
1

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 9.78
Variant links:
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
MAPTNM_001377265.1 linkuse as main transcriptc.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
MAPTENST00000262410.10 linkuse as main transcriptc.1991G>T p.Gly664Val missense_variant 9/131 NM_001377265.1 ENSP00000262410 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
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 providedliterature onlyOMIMMay 06, 2021- -
not provided Other:1
not provided, no classification providedliterature onlyVIB Department of Molecular Genetics, University of Antwerp-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;.;.;.;.;.;.;D;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D;.;.;.;.;.
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Uncertain
2.8
M;.;.;.;.;.;.;.;.;M;.;.
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-8.2
D;D;D;D;D;D;D;D;D;.;.;.
REVEL
Pathogenic
0.89
Sift
Uncertain
0.0070
D;D;D;D;D;D;D;D;D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;D;D;D;D;D;D;D;.
Vest4
0.79
MutPred
0.76
Loss of ubiquitination at K591 (P = 0.0598);.;.;.;.;.;.;.;.;Loss of ubiquitination at K591 (P = 0.0598);.;.;
MVP
1.0
MPC
2.3
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.94
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs63750376; hg19: chr17-44074023; API