rs62063787

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.1091T>C(p.Val364Ala) 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 1,613,954 control chromosomes in the GnomAD database, including 32,819 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2143 hom., cov: 33)

Exomes 𝑓: 0.19 ( 30676 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -0.0240

Publications

42 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=0.0047382116).

BP6

Variant 17-45983670-T-C is Benign according to our data. Variant chr17-45983670-T-C is described in ClinVar as Benign. ClinVar VariationId is 98200.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.1091T>C	p.Val364Ala	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.1091T>C	p.Val364Ala	missense_variant	Exon 5 of 13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22090

AN:

152132

Hom.:

2145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0742

Gnomad FIN

AF:

0.0649

Gnomad MID

AF:

0.220

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.186

GnomAD2 exomes

AF:

0.146

AC:

36543

AN:

251038

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0472

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0681

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.194

AC:

283025

AN:

1461704

Hom.:

30676

Cov.:

AF XY:

0.191

AC XY:

139002

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0431

AC:

1443

AN:

33480

American (AMR)

AF:

0.126

AC:

5618

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6699

AN:

26136

East Asian (EAS)

AF:

0.000882

AC:

AN:

39700

South Asian (SAS)

AF:

0.0796

AC:

6868

AN:

86256

European-Finnish (FIN)

AF:

0.0725

AC:

3863

AN:

53310

Middle Eastern (MID)

AF:

0.202

AC:

1165

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

246635

AN:

1111936

Other (OTH)

AF:

0.177

AC:

10699

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

14144

28288

42433

56577

70721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8234

16468

24702

32936

41170

<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:

0.145

AC:

22080

AN:

152250

Hom.:

2143

Cov.:

AF XY:

0.136

AC XY:

10127

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0493

AC:

2048

AN:

41570

American (AMR)

AF:

0.176

AC:

2689

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

834

AN:

3470

East Asian (EAS)

AF:

0.00155

AC:

AN:

5158

South Asian (SAS)

AF:

0.0742

AC:

358

AN:

4822

European-Finnish (FIN)

AF:

0.0649

AC:

690

AN:

10624

Middle Eastern (MID)

AF:

0.216

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.217

AC:

14751

AN:

67990

Other (OTH)

AF:

0.183

AC:

386

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

971

1943

2914

3886

4857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

238

476

714

952

1190

<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:

0.203

Hom.:

7165

Bravo

AF:

0.150

TwinsUK

AF:

0.232

AC:

861

ALSPAC

AF:

0.241

AC:

929

ESP6500AA

AF:

0.0515

AC:

227

ESP6500EA

AF:

0.224

AC:

1928

ExAC

AF:

0.145

AC:

17579

Asia WGS

AF:

0.0310

AC:

111

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

- -

Frontotemporal dementia

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.72

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.28

T;.;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.25

T;T;.;.

MetaRNN

Benign

0.0047

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.55

N;N;N;N

PhyloP100

-0.024

PrimateAI

Benign

0.23

PROVEAN

Benign

0.12

N;N;N;.

REVEL

Benign

0.061

Sift

Benign

1.0

T;T;T;.

Sift4G

Benign

0.92

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.022

MPC

0.18

ClinPred

0.00087

GERP RS

-1.4

Varity_R

0.026

gMVP

0.083

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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