rs2258689

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.1546T>C(p.Tyr516His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,613,896 control chromosomes in the GnomAD database, including 47,093 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y516Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.23 ( 4451 hom., cov: 32)

Exomes 𝑓: 0.23 ( 42642 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.17

Publications

65 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=1.1717118E-5).

BP6

Variant 17-45990016-T-C is Benign according to our data. Variant chr17-45990016-T-C is described in ClinVar as Benign. ClinVar VariationId is 98202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.1546T>C	p.Tyr516His	missense_variant	Exon 7 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.1546T>C	p.Tyr516His	missense_variant	Exon 7 of 13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34278

AN:

151986

Hom.:

4446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.296

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.228

GnomAD2 exomes

AF:

0.282

AC:

70858

AN:

251442

AF XY:

0.280

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.632

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.209

Gnomad OTH exome

AF:

0.263

GnomAD4 exome

AF:

0.227

AC:

331440

AN:

1461792

Hom.:

42642

Cov.:

AF XY:

0.230

AC XY:

167473

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.143

AC:

4775

AN:

33476

American (AMR)

AF:

0.366

AC:

16382

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

5465

AN:

26134

East Asian (EAS)

AF:

0.591

AC:

23473

AN:

39698

South Asian (SAS)

AF:

0.331

AC:

28571

AN:

86252

European-Finnish (FIN)

AF:

0.294

AC:

15705

AN:

53420

Middle Eastern (MID)

AF:

0.261

AC:

1506

AN:

5768

European-Non Finnish (NFE)

AF:

0.199

AC:

220949

AN:

1111932

Other (OTH)

AF:

0.242

AC:

14614

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

14970

29939

44909

59878

74848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7970

15940

23910

31880

39850

<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:

0.225

AC:

34296

AN:

152104

Hom.:

4451

Cov.:

AF XY:

0.234

AC XY:

17430

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.151

AC:

6254

AN:

41476

American (AMR)

AF:

0.297

AC:

4536

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

741

AN:

3468

East Asian (EAS)

AF:

0.624

AC:

3224

AN:

5164

South Asian (SAS)

AF:

0.346

AC:

1669

AN:

4818

European-Finnish (FIN)

AF:

0.289

AC:

3061

AN:

10580

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.208

AC:

14120

AN:

68008

Other (OTH)

AF:

0.235

AC:

495

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1301

2602

3902

5203

6504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.215

Hom.:

13617

Bravo

AF:

0.223

TwinsUK

AF:

0.192

AC:

713

ALSPAC

AF:

0.189

AC:

730

ESP6500AA

AF:

0.148

AC:

651

ESP6500EA

AF:

0.198

AC:

1707

ExAC

AF:

0.275

AC:

33402

Asia WGS

AF:

0.509

AC:

1767

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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

- -

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 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Frontotemporal dementia

Benign:1

Jan 06, 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

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.30

T;.;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.55

T;T;.;.

MetaRNN

Benign

0.000012

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.3

N;N;N;N

PhyloP100

1.2

PrimateAI

Benign

0.46

PROVEAN

Benign

1.2

N;N;N;.

REVEL

Benign

0.034

Sift

Benign

0.93

T;T;T;.

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.069

MPC

0.20

ClinPred

0.0017

GERP RS

1.8

Varity_R

0.034

gMVP

0.089

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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