rs10445337

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.1564T>C(p.Ser522Pro) 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 1,613,906 control chromosomes in the GnomAD database, including 32,818 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 0.14 ( 2147 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30671 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.05

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=0.0015476942).

BP6

Variant 17-45990034-T-C is Benign according to our data. Variant chr17-45990034-T-C is described in ClinVar as Benign. ClinVar VariationId is 98203.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377265.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAPT	NM_001377265.1	MANE Select	c.1564T>C	p.Ser522Pro	missense	Exon 7 of 13	NP_001364194.1
MAPT	NM_001123066.4		c.1339T>C	p.Ser447Pro	missense	Exon 8 of 15	NP_001116538.2
MAPT	NM_016835.5		c.1339T>C	p.Ser447Pro	missense	Exon 8 of 14	NP_058519.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1564T>C	p.Ser522Pro	missense	Exon 7 of 13	ENSP00000262410.6
MAPT	ENST00000344290.10	TSL:1	c.1408-1426T>C		intron	N/A	ENSP00000340820.6
MAPT	ENST00000351559.10	TSL:1	c.430-1426T>C		intron	N/A	ENSP00000303214.7

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22074

AN:

152084

Hom.:

2149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0492

Gnomad AMI

AF:

0.276

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0741

Gnomad FIN

AF:

0.0652

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.186

GnomAD2 exomes

AF:

0.146

AC:

36637

AN:

251458

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.0474

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000652

Gnomad FIN exome

AF:

0.0681

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.194

AC:

282964

AN:

1461704

Hom.:

30671

Cov.:

AF XY:

0.191

AC XY:

138977

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.0431

AC:

1443

AN:

33480

American (AMR)

AF:

0.126

AC:

5613

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6698

AN:

26134

East Asian (EAS)

AF:

0.000882

AC:

AN:

39698

South Asian (SAS)

AF:

0.0796

AC:

6869

AN:

86256

European-Finnish (FIN)

AF:

0.0724

AC:

3868

AN:

53418

Middle Eastern (MID)

AF:

0.202

AC:

1165

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

246576

AN:

1111840

Other (OTH)

AF:

0.177

AC:

10697

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

12128

24256

36384

48512

60640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8230

16460

24690

32920

41150

<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:

22064

AN:

152202

Hom.:

2147

Cov.:

AF XY:

0.136

AC XY:

10119

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0491

AC:

2039

AN:

41528

American (AMR)

AF:

0.175

AC:

2679

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

831

AN:

3468

East Asian (EAS)

AF:

0.00154

AC:

AN:

5186

South Asian (SAS)

AF:

0.0742

AC:

358

AN:

4826

European-Finnish (FIN)

AF:

0.0652

AC:

692

AN:

10618

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14755

AN:

67990

Other (OTH)

AF:

0.183

AC:

388

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

922

1844

2767

3689

4611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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.:

7395

Bravo

AF:

0.150

TwinsUK

AF:

0.234

AC:

866

ALSPAC

AF:

0.242

AC:

932

ESP6500AA

AF:

0.0511

AC:

225

ESP6500EA

AF:

0.223

AC:

1917

ExAC

AF:

0.145

AC:

17587

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Frontotemporal dementia (2)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.28

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.6

PhyloP100

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

0.78

REVEL

Benign

0.064

Sift

Benign

1.0

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.076

MPC

0.19

ClinPred

0.0014

GERP RS

4.1

Varity_R

0.067

gMVP

0.052

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over