rs114635790

Positions:

chr17-45991482-T-C

Variant summary

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

The NM_001377265.1(MAPT):c.1628T>C(p.Ile543Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,614,142 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I543M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.18

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=0.0035247207).

BP6

Variant 17-45991482-T-C is Benign according to our data. Variant chr17-45991482-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 529748.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 = 0.00196 (298/152254) while in subpopulation AFR AF= 0.00662 (275/41546). AF 95% confidence interval is 0.00598. There are 2 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.1628T>C	p.Ile543Thr	missense_variant	8/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10 linkuse as main transcript	c.1628T>C	p.Ile543Thr	missense_variant	8/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

297

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00661

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000553

AC:

139

AN:

251316

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000238

AC:

348

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00693

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.00196

AC:

298

AN:

152254

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00662

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000431

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000791

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Frontotemporal dementia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

MAPT-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.29

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.0072

MetaRNN

Benign

0.0035

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

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

MutationTaster

Benign

0.65

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

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.65

N;N;N;N;N;N;N;N;N;.;.;D

REVEL

Benign

0.060

Sift

Benign

0.15

T;T;T;T;T;T;T;T;T;.;.;D

Sift4G

Benign

0.80

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

Polyphen

0.37

B;B;B;.;D;B;B;D;B;B;B;.

Vest4

0.14

MVP

0.64

MPC

0.20

ClinPred

0.0064

GERP RS

4.1

Varity_R

0.035

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