rs17651549

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001377265.1(MAPT):c.1333C>T(p.Arg445Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,573,970 control chromosomes in the GnomAD database, including 32,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2118 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29992 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.86

Publications

81 publications found

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 Gene-Disease associations (from GenCC):

Pick disease
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
semantic dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
supranuclear palsy, progressive, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
late-onset Parkinson disease
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
progressive supranuclear palsy-parkinsonism syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

MAPT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001711458).

BP6

Variant 17-45983912-C-T is Benign according to our data. Variant chr17-45983912-C-T is described in ClinVar as Benign. ClinVar VariationId is 257502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.1333C>T	p.Arg445Trp	missense_variant	Exon 5 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 link	c.1333C>T	p.Arg445Trp	missense_variant	Exon 5 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21648

AN:

152120

Hom.:

2120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0392

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0739

Gnomad FIN

AF:

0.0651

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.147

AC:

31553

AN:

214722

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.259

Gnomad EAS exome

AF:

0.000558

Gnomad FIN exome

AF:

0.0685

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.194

AC:

276314

AN:

1421732

Hom.:

29992

Cov.:

AF XY:

0.192

AC XY:

135321

AN XY:

704920

show subpopulations

African (AFR)

AF:

0.0321

AC:

1006

AN:

31296

American (AMR)

AF:

0.127

AC:

4564

AN:

35820

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6064

AN:

23704

East Asian (EAS)

AF:

0.000914

AC:

AN:

39406

South Asian (SAS)

AF:

0.0795

AC:

6381

AN:

80284

European-Finnish (FIN)

AF:

0.0725

AC:

3725

AN:

51408

Middle Eastern (MID)

AF:

0.202

AC:

1112

AN:

5512

European-Non Finnish (NFE)

AF:

0.222

AC:

243113

AN:

1095906

Other (OTH)

AF:

0.177

AC:

10313

AN:

58396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11522

23044

34566

46088

57610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8204

16408

24612

32816

41020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.142

AC:

21635

AN:

152238

Hom.:

2118

Cov.:

AF XY:

0.133

AC XY:

9898

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0390

AC:

1622

AN:

41564

American (AMR)

AF:

0.175

AC:

2683

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

833

AN:

3470

East Asian (EAS)

AF:

0.00155

AC:

AN:

5154

South Asian (SAS)

AF:

0.0739

AC:

357

AN:

4830

European-Finnish (FIN)

AF:

0.0651

AC:

692

AN:

10624

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14745

AN:

67984

Other (OTH)

AF:

0.181

AC:

382

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

931

1862

2793

3724

4655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.193

Hom.:

12261

Bravo

AF:

0.147

TwinsUK

AF:

0.233

AC:

865

ALSPAC

AF:

0.242

AC:

931

ESP6500AA

AF:

0.0415

AC:

171

ESP6500EA

AF:

0.216

AC:

1750

ExAC

AF:

0.143

AC:

17269

Asia WGS

AF:

0.0300

AC:

106

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Frontotemporal dementia

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23222517) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;.;.;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.82

T;T;.;.

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L;L

PhyloP100

2.9

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.6

D;N;N;.

REVEL

Benign

0.14

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.34

MPC

0.66

ClinPred

0.041

GERP RS

4.5

Varity_R

0.22

gMVP

0.26

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over