chr17-45983409-C-T

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.830C>T(p.Pro277Leu) 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 1,606,114 control chromosomes in the GnomAD database, including 32,668 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2145 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30523 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.432

Publications

52 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=0.0061332285).

BP6

Variant 17-45983409-C-T is Benign according to our data. Variant chr17-45983409-C-T is described in ClinVar as Benign. ClinVar VariationId is 98244.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.830C>T	p.Pro277Leu	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.830C>T	p.Pro277Leu	missense_variant	Exon 5 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22080

AN:

152104

Hom.:

2147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0492

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0738

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:

35042

AN:

239580

AF XY:

0.150

show subpopulations

Gnomad AFR exome

AF:

0.0481

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.257

Gnomad EAS exome

AF:

0.000661

Gnomad FIN exome

AF:

0.0691

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.178

GnomAD4 exome

AF:

0.194

AC:

281770

AN:

1453892

Hom.:

30523

Cov.:

AF XY:

0.191

AC XY:

138180

AN XY:

722234

show subpopulations

African (AFR)

AF:

0.0430

AC:

1432

AN:

33300

American (AMR)

AF:

0.125

AC:

5538

AN:

44166

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6634

AN:

25872

East Asian (EAS)

AF:

0.000885

AC:

AN:

39550

South Asian (SAS)

AF:

0.0798

AC:

6845

AN:

85758

European-Finnish (FIN)

AF:

0.0725

AC:

3771

AN:

52026

Middle Eastern (MID)

AF:

0.202

AC:

1155

AN:

5724

European-Non Finnish (NFE)

AF:

0.222

AC:

245727

AN:

1107568

Other (OTH)

AF:

0.177

AC:

10633

AN:

59928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

14296

28591

42887

57182

71478

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:

22070

AN:

152222

Hom.:

2145

Cov.:

AF XY:

0.136

AC XY:

10132

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0491

AC:

2038

AN:

41544

American (AMR)

AF:

0.176

AC:

2693

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

834

AN:

3472

East Asian (EAS)

AF:

0.00154

AC:

AN:

5180

South Asian (SAS)

AF:

0.0738

AC:

356

AN:

4822

European-Finnish (FIN)

AF:

0.0652

AC:

692

AN:

10614

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14747

AN:

67974

Other (OTH)

AF:

0.183

AC:

387

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

961

1921

2882

3842

4803

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:

0.172

Hom.:

1755

Bravo

AF:

0.150

TwinsUK

AF:

0.233

AC:

864

ESP6500AA

AF:

0.0510

AC:

220

ESP6500EA

AF:

0.222

AC:

1886

ExAC

AF:

0.144

AC:

17428

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

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

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: 30679340, 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

0.069

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

T;.;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.76

LIST_S2

Benign

0.65

T;T;.;.

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L;L;L

PhyloP100

0.43

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

N;N;N;.

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.0080

D;D;D;D

Vest4

0.11

ClinPred

0.012

GERP RS

-0.93

Varity_R

0.049

gMVP

0.11

Mutation Taster

=99/1

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