Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001377265.1(MAPT):c.862G>A(p.Gly288Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,606,902 control chromosomes in the GnomAD database, including 69 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 36 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.180

Publications

13 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=0.0036166906).

BP6

Variant 17-45983441-G-A is Benign according to our data. Variant chr17-45983441-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1583/152306) while in subpopulation AFR AF = 0.0328 (1364/41578). AF 95% confidence interval is 0.0314. There are 33 homozygotes in GnomAd4. There are 710 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 Unknown,AR,AD gene

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.862G>A	p.Gly288Arg	missense	Exon 5 of 13	NP_001364194.1
MAPT	NM_001123066.4		c.637G>A	p.Gly213Arg	missense	Exon 6 of 15	NP_001116538.2
MAPT	NM_016835.5		c.637G>A	p.Gly213Arg	missense	Exon 6 of 14	NP_058519.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAPT	ENST00000262410.10	TSL:1 MANE Select	c.862G>A	p.Gly288Arg	missense	Exon 5 of 13	ENSP00000262410.6
MAPT	ENST00000344290.10	TSL:1	c.862G>A	p.Gly288Arg	missense	Exon 5 of 11	ENSP00000340820.6
MAPT	ENST00000351559.10	TSL:1	c.374-3599G>A		intron	N/A	ENSP00000303214.7

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1562

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00342

AC:

826

AN:

241626

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.00376

Gnomad ASJ exome

AF:

0.00125

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00192

AC:

2800

AN:

1454596

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1279

AN XY:

722666

show subpopulations

African (AFR)

AF:

0.0324

AC:

1080

AN:

33294

American (AMR)

AF:

0.00433

AC:

192

AN:

44340

Ashkenazi Jewish (ASJ)

AF:

0.00108

AC:

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.000221

AC:

AN:

85794

European-Finnish (FIN)

AF:

0.0000768

AC:

AN:

52104

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00103

AC:

1144

AN:

1107944

Other (OTH)

AF:

0.00453

AC:

272

AN:

60034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

175

350

524

699

874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.0104

AC:

1583

AN:

152306

Hom.:

Cov.:

AF XY:

0.00953

AC XY:

710

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0328

AC:

1364

AN:

41578

American (AMR)

AF:

0.00758

AC:

116

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

68016

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00448

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0285

AC:

125

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00384

AC:

466

Asia WGS

AF:

0.00520

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Frontotemporal dementia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

0.18

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

REVEL

Benign

0.027

Sift

Benign

0.056

Sift4G

Benign

0.63

Polyphen

1.0

Vest4

0.10

MutPred

0.33

Gain of solvent accessibility (P = 0.0037)

MVP

0.63

MPC

0.25

ClinPred

0.025

GERP RS

1.1

Varity_R

0.044

gMVP

0.087

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs76375268

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