Genetic Variant MAPT:p.Pro662Pro (chr17-45996652-G-A) – 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.1986G>A(p.Pro662Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.041 in 1,613,756 control chromosomes in the GnomAD database, including 1,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 120 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1418 hom. )

Consequence

MAPT
NM_001377265.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.86

Publications

17 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):

late-onset Parkinson disease
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Pick disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
semantic dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
supranuclear palsy, progressive, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
progressive supranuclear palsy-parkinsonism syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

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=-0.77).

BP6

Variant 17-45996652-G-A is Benign according to our data. Variant chr17-45996652-G-A is described in ClinVar as Benign. ClinVar VariationId is 98211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.86 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.104 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	UniProt
MAPT	NM_001377265.1	MANE Select	c.1986G>A	p.Pro662Pro	synonymous	Exon 9 of 13	NP_001364194.1	A0A7I2PJZ2
MAPT	NM_001123066.4		c.1815G>A	p.Pro605Pro	synonymous	Exon 11 of 15	NP_001116538.2	P10636-9
MAPT	NM_016835.5		c.1761G>A	p.Pro587Pro	synonymous	Exon 10 of 14	NP_058519.3	P10636-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPT	ENST00000262410.10	TSL:1 MANE Select	c.1986G>A	p.Pro662Pro	synonymous	Exon 9 of 13	ENSP00000262410.6	A0A7I2PJZ2
MAPT	ENST00000344290.10	TSL:1	c.1788G>A	p.Pro596Pro	synonymous	Exon 8 of 11	ENSP00000340820.6	A0A7I2PLE3
MAPT	ENST00000351559.10	TSL:1	c.810G>A	p.Pro270Pro	synonymous	Exon 8 of 12	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5900

AN:

152108

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0346

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0367

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0154

Gnomad SAS

AF:

0.0383

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0444

Gnomad OTH

AF:

0.0508

GnomAD2 exomes

AF:

0.0352

AC:

8719

AN:

247630

AF XY:

0.0367

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.0221

Gnomad ASJ exome

AF:

0.0474

Gnomad EAS exome

AF:

0.0157

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0419

Gnomad OTH exome

AF:

0.0504

GnomAD4 exome

AF:

0.0412

AC:

60185

AN:

1461530

Hom.:

1418

Cov.:

AF XY:

0.0415

AC XY:

30148

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0370

AC:

1239

AN:

33476

American (AMR)

AF:

0.0238

AC:

1064

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0454

AC:

1186

AN:

26128

East Asian (EAS)

AF:

0.0166

AC:

659

AN:

39688

South Asian (SAS)

AF:

0.0414

AC:

3572

AN:

86244

European-Finnish (FIN)

AF:

0.0256

AC:

1364

AN:

53278

Middle Eastern (MID)

AF:

0.111

AC:

642

AN:

5768

European-Non Finnish (NFE)

AF:

0.0430

AC:

47771

AN:

1111862

Other (OTH)

AF:

0.0445

AC:

2688

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

3626

7253

10879

14506

18132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1764

3528

5292

7056

8820

<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:

0.0388

AC:

5903

AN:

152226

Hom.:

120

Cov.:

AF XY:

0.0382

AC XY:

2840

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0346

AC:

1437

AN:

41548

American (AMR)

AF:

0.0366

AC:

560

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

160

AN:

3472

East Asian (EAS)

AF:

0.0155

AC:

AN:

5178

South Asian (SAS)

AF:

0.0389

AC:

187

AN:

4806

European-Finnish (FIN)

AF:

0.0239

AC:

254

AN:

10612

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0444

AC:

3019

AN:

68008

Other (OTH)

AF:

0.0502

AC:

106

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

284

568

852

1136

1420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0390

Hom.:

Bravo

AF:

0.0396

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.0467

EpiControl

AF:

0.0433

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Frontotemporal dementia (1)

MAPT-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.16

(source)

DANN

Benign

0.86

PhyloP100

-3.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over