rs63750612

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001377265.1(MAPT):c.1708G>A(p.Ala570Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,614,058 control chromosomes in the GnomAD database, including 100 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 0.014 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 56 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.997

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=0.0019565523).

BP6

Variant 17-45991562-G-A is Benign according to our data. Variant chr17-45991562-G-A is described in ClinVar as [Benign]. Clinvar id is 98205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45991562-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2152/152232) while in subpopulation AFR AF= 0.0491 (2040/41524). AF 95% confidence interval is 0.0474. There are 44 homozygotes in gnomad4. There are 1000 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.1708G>A	p.Ala570Thr	missense_variant	8/13	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.1708G>A	p.Ala570Thr	missense_variant	8/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2154

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0493

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00550

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00910

GnomAD3 exomes

AF:

0.00364

AC:

915

AN:

251212

Hom.:

AF XY:

0.00264

AC XY:

359

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00141

AC:

2061

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

851

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0499

Gnomad4 AMR exome

AF:

0.00302

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.00321

GnomAD4 genome

AF:

0.0141

AC:

2152

AN:

152232

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

1000

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0491

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00253

Hom.:

Bravo

AF:

0.0162

ESP6500AA

AF:

0.0454

AC:

200

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00421

AC:

511

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2018	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

MAPT-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.28

DANN

Benign

0.85

DEOGEN2

Benign

0.28

T;.;.;.;.;.;.;.;.;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.83

T;T;T;T;T;T;T;.;.;.;.;.

MetaRNN

Benign

0.0020

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.41

N;.;N;.;.;.;.;.;N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.47

N;N;N;N;N;N;N;N;N;.;.;.

REVEL

Benign

0.0050

Sift

Benign

0.43

T;T;T;T;T;T;T;T;T;.;.;.

Sift4G

Benign

0.69

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.010

B;B;B;.;B;B;B;B;B;B;B;.

Vest4

0.029

MVP

0.30

MPC

0.15

ClinPred

0.0023

GERP RS

-8.8

Varity_R

0.026

gMVP

0.14

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