rs63750424

Positions:

chr17-46024061-C-T

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 2.20

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]

MAPT links:

Genome browser will be placed here

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	Protein	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.2392C>T	p.Arg798Trp	missense_variant	13/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 linkuse as main transcript	c.2392C>T	p.Arg798Trp	missense_variant	13/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251284

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000182

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2023	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 (PMID: 11756436, 10820221); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23105105, 30279455, 30562452, 31836585, 29370822, 33061333, 34158384, 33427744, 23383383, 22368988, 18803694, 10820221, 24150109, 20634584, 23338682, 19304664, 21339331, 11102510, 18992292, 21849646, 22787795, 20377816, 26581847, 26028272, 25377499, 26734663, 25942996, 29253099, 11278002, 12368474, 11889249, 18284428, 9641683, 14517953, 10514099, 18587238, 20683187, 23727082, 31127772, 30924900, 32843152, 20662935, 11756436) -
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, 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	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	Labcorp Genetics (formerly Invitae), Labcorp	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

- -

MAPT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The MAPT c.2221C>T variant is predicted to result in the amino acid substitution p.Arg741Trp. The variant is also referred to as c.1216C>T (p.Arg406Trp) using a different transcript (NM_005910.5). This variant has been extensively reported in individuals with behavioral variant frontotemporal dementia (bvFTD), Alzheimer Disease, or dementia with parkinsonism (Tipton et al. 2022. PubMed ID: 35790423; Koriath et al. 2020. PubMed ID: 30279455; Kunkle et al. 2017. PubMed ID: 28738127). For example, this variant has been reported in the heterozygous state to be causative of frontotemporal dementia in a large family with a history of the disease (Hutton et al. 1998. PubMed ID: 9641683). It was also reported in the heterozygous state to be pathogenic in a large family with early-onset Alzheimer Disease (EOAD)-like presentation (Carney et al. 2014. PubMed ID: 23727082). One report described this variant in the homozygous state in an individual with early-onset bvFTD who developed symptoms 20 years before mean family symptom onset, suggesting a dose-dependent effect on disease risk (Ng et al. 2015. PMID: 26734663). It is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD; and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14247/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.;.;.;.;.;.;D;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;.;.;.;.;.

M_CAP

Benign

0.027

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.5

L;.;.;.;.;.;.;.;.;L;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.2

D;D;D;D;D;.;.;D;D;.;.;.

REVEL

Benign

0.29

Sift

Uncertain

0.013

D;D;D;D;D;.;.;D;D;.;.;.

Sift4G

Pathogenic

0.0010

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

0.17

MutPred

0.42

Loss of disorder (P = 0.0292);.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0292);.;.;

MVP

0.84

MPC

2.1

ClinPred

0.98

GERP RS

3.4

Varity_R

0.78

gMVP

0.77

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over