17-45983757-C-T

Position:

chr17-45983757-C-T

Variant summary

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

The ENST00000262410.10(MAPT):c.1178C>T(p.Ser393Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0105 in 1,614,056 control chromosomes in the GnomAD database, including 1,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S393S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.052 ( 715 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 610 hom. )

Consequence

MAPT
ENST00000262410.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.83

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=0.0020686686).

BP6

Variant 17-45983757-C-T is Benign according to our data. Variant chr17-45983757-C-T is described in ClinVar as [Benign]. Clinvar id is 257505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45983757-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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.1178C>T	p.Ser393Leu	missense_variant	5/13	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.1178C>T	p.Ser393Leu	missense_variant	5/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes

AF:

0.0517

AC:

7872

AN:

152138

Hom.:

711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0199

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.0382

GnomAD3 exomes

AF:

0.0143

AC:

3573

AN:

250466

Hom.:

264

AF XY:

0.0109

AC XY:

1481

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00139

Gnomad OTH exome

AF:

0.00950

GnomAD4 exome

AF:

0.00614

AC:

8969

AN:

1461800

Hom.:

610

Cov.:

AF XY:

0.00546

AC XY:

3971

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.184

Gnomad4 AMR exome

AF:

0.0121

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000417

Gnomad4 FIN exome

AF:

0.0000937

Gnomad4 NFE exome

AF:

0.00115

Gnomad4 OTH exome

AF:

0.0139

GnomAD4 genome

AF:

0.0519

AC:

7898

AN:

152256

Hom.:

715

Cov.:

AF XY:

0.0496

AC XY:

3690

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.178

Gnomad4 AMR

AF:

0.0199

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00141

Gnomad4 OTH

AF:

0.0378

Alfa

AF:

0.00792

Hom.:

112

Bravo

AF:

0.0590

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.172

AC:

759

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.0171

AC:

2082

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	This variant is associated with the following publications: (PMID: 23990795, 27884173) -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Frontotemporal dementia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;.;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.70

T;T;.;.

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;L

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.66

N;N;N;.

REVEL

Benign

0.046

Sift

Benign

0.19

T;T;T;.

Sift4G

Benign

0.38

T;T;T;T

Polyphen

0.26

B;B;B;B

Vest4

0.23

MPC

0.13

ClinPred

0.020

GERP RS

4.4

Varity_R

0.076

gMVP

0.15

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