rs2258689

Positions:

chr17-45990016-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001377265.1(MAPT):c.1546T>C(p.Tyr516His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,613,896 control chromosomes in the GnomAD database, including 47,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4451 hom., cov: 32)

Exomes 𝑓: 0.23 ( 42642 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1717118E-5).

BP6

Variant 17-45990016-T-C is Benign according to our data. Variant chr17-45990016-T-C is described in ClinVar as [Benign]. Clinvar id is 98202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45990016-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.1546T>C	p.Tyr516His	missense_variant	7/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 linkuse as main transcript	c.1546T>C	p.Tyr516His	missense_variant	7/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34278

AN:

151986

Hom.:

4446

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.296

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.624

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.289

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.208

Gnomad OTH

AF:

0.228

GnomAD3 exomes

AF:

0.282

AC:

70858

AN:

251442

Hom.:

11999

AF XY:

0.280

AC XY:

38064

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.632

Gnomad SAS exome

AF:

0.329

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.209

Gnomad OTH exome

AF:

0.263

GnomAD4 exome

AF:

0.227

AC:

331440

AN:

1461792

Hom.:

42642

Cov.:

AF XY:

0.230

AC XY:

167473

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.366

Gnomad4 ASJ exome

AF:

0.209

Gnomad4 EAS exome

AF:

0.591

Gnomad4 SAS exome

AF:

0.331

Gnomad4 FIN exome

AF:

0.294

Gnomad4 NFE exome

AF:

0.199

Gnomad4 OTH exome

AF:

0.242

GnomAD4 genome

AF:

0.225

AC:

34296

AN:

152104

Hom.:

4451

Cov.:

AF XY:

0.234

AC XY:

17430

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.151

Gnomad4 AMR

AF:

0.297

Gnomad4 ASJ

AF:

0.214

Gnomad4 EAS

AF:

0.624

Gnomad4 SAS

AF:

0.346

Gnomad4 FIN

AF:

0.289

Gnomad4 NFE

AF:

0.208

Gnomad4 OTH

AF:

0.235

Alfa

AF:

0.215

Hom.:

8671

Bravo

AF:

0.223

TwinsUK

AF:

0.192

AC:

713

ALSPAC

AF:

0.189

AC:

730

ESP6500AA

AF:

0.148

AC:

651

ESP6500EA

AF:

0.198

AC:

1707

ExAC

AF:

0.275

AC:

33402

Asia WGS

AF:

0.509

AC:

1767

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Frontotemporal dementia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.30

T;.;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.55

T;T;.;.

MetaRNN

Benign

0.000012

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.3

N;N;N;N

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

1.2

N;N;N;.

REVEL

Benign

0.034

Sift

Benign

0.93

T;T;T;.

Sift4G

Benign

0.60

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.069

MPC

0.20

ClinPred

0.0017

GERP RS

1.8

Varity_R

0.034

gMVP

0.089

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over