dbSNP rs17652121: MAPT:p.Asn647Asn (chr17-45996607-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001377265.1(MAPT):c.1941T>C(p.Asn647Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,412 control chromosomes in the GnomAD database, including 32,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2148 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30650 hom. )

Consequence

MAPT
NM_001377265.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.0740

Publications

69 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 17-45996607-T-C is Benign according to our data. Variant chr17-45996607-T-C is described in ClinVar as Benign. ClinVar VariationId is 98209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.074 with no splicing effect.

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.1941T>C	p.Asn647Asn	synonymous	Exon 9 of 13	NP_001364194.1
MAPT	NM_001123066.4		c.1770T>C	p.Asn590Asn	synonymous	Exon 11 of 15	NP_001116538.2
MAPT	NM_016835.5		c.1716T>C	p.Asn572Asn	synonymous	Exon 10 of 14	NP_058519.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1941T>C	p.Asn647Asn	synonymous	Exon 9 of 13	ENSP00000262410.6
MAPT	ENST00000344290.10	TSL:1	c.1743T>C	p.Asn581Asn	synonymous	Exon 8 of 11	ENSP00000340820.6
MAPT	ENST00000351559.10	TSL:1	c.765T>C	p.Asn255Asn	synonymous	Exon 8 of 12	ENSP00000303214.7

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22053

AN:

151688

Hom.:

2150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0493

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.0731

Gnomad FIN

AF:

0.0652

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.145

AC:

36129

AN:

249222

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:

0.0680

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.194

AC:

282944

AN:

1461610

Hom.:

30650

Cov.:

AF XY:

0.191

AC XY:

138962

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.0429

AC:

1435

AN:

33476

American (AMR)

AF:

0.125

AC:

5612

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.256

AC:

6699

AN:

26130

East Asian (EAS)

AF:

0.000907

AC:

AN:

39694

South Asian (SAS)

AF:

0.0796

AC:

6865

AN:

86250

European-Finnish (FIN)

AF:

0.0724

AC:

3858

AN:

53324

Middle Eastern (MID)

AF:

0.202

AC:

1165

AN:

5768

European-Non Finnish (NFE)

AF:

0.222

AC:

246580

AN:

1111874

Other (OTH)

AF:

0.177

AC:

10694

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

13641

27283

40924

54566

68207

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:

22043

AN:

151802

Hom.:

2148

Cov.:

AF XY:

0.136

AC XY:

10110

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.0492

AC:

2038

AN:

41404

American (AMR)

AF:

0.176

AC:

2678

AN:

15236

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

832

AN:

3466

East Asian (EAS)

AF:

0.00155

AC:

AN:

5152

South Asian (SAS)

AF:

0.0732

AC:

351

AN:

4794

European-Finnish (FIN)

AF:

0.0652

AC:

688

AN:

10550

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.217

AC:

14746

AN:

67894

Other (OTH)

AF:

0.184

AC:

386

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

906

1812

2717

3623

4529

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.190

Hom.:

6815

Bravo

AF:

0.150

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 25, 2011

Athena Diagnostics

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

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

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAPT-Related Spectrum Disorders

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Frontotemporal dementia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.9

(source)

DANN

Benign

0.59

PhyloP100

-0.074

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over