chr17-45983493-A-G

Position:

chr17-45983493-A-G

Variant summary

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

The NM_001377265.1(MAPT):c.914A>G(p.Gln305Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,611,384 control chromosomes in the GnomAD database, including 2,247 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 144 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2103 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 2.48

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=0.003071189).

BP6

Variant 17-45983493-A-G is Benign according to our data. Variant chr17-45983493-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 98197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45983493-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.914A>G	p.Gln305Arg	missense_variant	5/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10 linkuse as main transcript	c.914A>G	p.Gln305Arg	missense_variant	5/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes

AF:

0.0389

AC:

5911

AN:

152038

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.0702

Gnomad AMR

AF:

0.0399

Gnomad ASJ

AF:

0.0260

Gnomad EAS

AF:

0.0151

Gnomad SAS

AF:

0.0437

Gnomad FIN

AF:

0.0263

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0567

Gnomad OTH

AF:

0.0559

GnomAD3 exomes

AF:

0.0396

AC:

9703

AN:

244776

Hom.:

247

AF XY:

0.0420

AC XY:

5608

AN XY:

133426

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0304

Gnomad EAS exome

AF:

0.0157

Gnomad SAS exome

AF:

0.0468

Gnomad FIN exome

AF:

0.0260

Gnomad NFE exome

AF:

0.0528

Gnomad OTH exome

AF:

0.0583

GnomAD4 exome

AF:

0.0500

AC:

72947

AN:

1459228

Hom.:

2103

Cov.:

AF XY:

0.0503

AC XY:

36521

AN XY:

725738

show subpopulations

Gnomad4 AFR exome

AF:

0.0121

Gnomad4 AMR exome

AF:

0.0267

Gnomad4 ASJ exome

AF:

0.0288

Gnomad4 EAS exome

AF:

0.0147

Gnomad4 SAS exome

AF:

0.0473

Gnomad4 FIN exome

AF:

0.0293

Gnomad4 NFE exome

AF:

0.0546

Gnomad4 OTH exome

AF:

0.0498

GnomAD4 genome

AF:

0.0388

AC:

5908

AN:

152156

Hom.:

144

Cov.:

AF XY:

0.0375

AC XY:

2790

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0134

Gnomad4 AMR

AF:

0.0398

Gnomad4 ASJ

AF:

0.0260

Gnomad4 EAS

AF:

0.0151

Gnomad4 SAS

AF:

0.0444

Gnomad4 FIN

AF:

0.0263

Gnomad4 NFE

AF:

0.0567

Gnomad4 OTH

AF:

0.0553

Alfa

AF:

0.0522

Hom.:

400

Bravo

AF:

0.0389

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0516

AC:

199

ESP6500AA

AF:

0.0160

AC:

ESP6500EA

AF:

0.0551

AC:

471

ExAC

AF:

0.0392

AC:

4750

Asia WGS

AF:

0.0310

AC:

107

AN:

3478

EpiCase

AF:

0.0623

EpiControl

AF:

0.0565

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	This variant is associated with the following publications: (PMID: 29339765) -

Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

Frontotemporal dementia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;.;T

Eigen

Benign

0.066

Eigen_PC

Benign

-0.050

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.65

T;T;.;.

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

N;N;N;.

REVEL

Benign

0.079

Sift

Uncertain

0.0020

D;D;D;.

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.99

D;D;D;D

Vest4

0.095

MPC

0.17

ClinPred

0.019

GERP RS

4.1

Varity_R

0.090

gMVP

0.12

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

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