rs143624519

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001377265.1(MAPT):c.1630G>A(p.Ala544Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,614,188 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 10 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.70

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009972304).

BP6

Variant 17-45991484-G-A is Benign according to our data. Variant chr17-45991484-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 323645.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}. Variant chr17-45991484-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00181 (276/152302) while in subpopulation NFE AF= 0.00304 (207/68022). AF 95% confidence interval is 0.0027. There are 1 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.1630G>A	p.Ala544Thr	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.1630G>A	p.Ala544Thr	missense_variant	8/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00304

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00151

AC:

380

AN:

251282

Hom.:

AF XY:

0.00154

AC XY:

209

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00230

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00275

AC:

4025

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

1927

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00101

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00325

Gnomad4 OTH exome

AF:

0.00343

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152302

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00304

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00260

Hom.:

Bravo

AF:

0.00179

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MAPT: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2019	This variant is associated with the following publications: (PMID: 26916334, 29525180, 27594585, 28594853, 28334843, 23518664, 24319659, 26931569, 27776828, 26333800, 21176711, 23692670, 22312439, 23990795, 22595371, 22556362, 22906081, 30279455) -

Frontotemporal dementia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 152 of the MAPT protein (p.Ala152Thr). This variant is present in population databases (rs143624519, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Parkinson disease, frontotemporal dementia (FTD), or Alzheimer disease (AD), however this variant has also been reported in control populations. A single study found that this variant increases the risk for both FTD (OR =3.0, CI: 1.6‚Äì5.6, P= 0.0005) and AD (OR=2.3, CI: 1.3‚Äì4.2, P=0.004), but this result has not been independently replicated (PMID: 21176711, 22312439, 22556362, 22595371, 22906081, 23518664, 26333800, 33612544). It has also been observed to segregate with disease in related individuals. This variant is also known as NM_016835.4:c.1405G>A p.(Ala469Thr). ClinVar contains an entry for this variant (Variation ID: 323645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAPT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAPT function (PMID: 22556362, 26931567, 28334843). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 26, 2024

- -

MAPT-Related Spectrum Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.45

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

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

D;D;D;D;D;D;D;.;.;.;.;.

M_CAP

Benign

0.0075

MetaRNN

Benign

0.010

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;L;.;.;.;.;.;L;L;.;.

MutationTaster

Benign

0.58

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

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.016

Sift

Benign

0.040

D;D;D;D;D;D;D;D;D;.;.;.

Sift4G

Benign

0.15

T;T;D;T;T;T;T;T;D;T;T;T

Polyphen

0.70

P;B;B;.;P;B;B;P;B;P;B;.

Vest4

0.11

MVP

0.63

MPC

0.21

ClinPred

0.058

GERP RS

3.1

Varity_R

0.057

gMVP

0.27

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