rs143624519

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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).

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 P:1U: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 -9 ACMG points.

BP4

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

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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.1630G>A	p.Ala544Thr	missense_variant	Exon 8 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 link	c.1630G>A	p.Ala544Thr	missense_variant	Exon 8 of 13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

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: Pathogenic:1Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Mar 29, 2024

Athena Diagnostics

Significance: Likely risk allele

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to cause an increased risk of developing clinical features associated with this gene. This variant is statistically more frequent in individuals affected with frontotemporal dementia (FTD) and Alzheimer disease (AD) than in the general population and/or healthy controls (PMID: 22556362), even though its frequency in the general population is higher than would generally be expected for pathogenic variants in this gene (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) It has been reported in multiple studies that Ala152Thr is associated with a wide range of diagnoses, including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinsonism, progressive supranuclear palsy (PSP), and others. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 26916334, 26931567, 26931569, 30590647, 28334843) -

Mar 27, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAPT: BP4, BS2 -

Frontotemporal dementia

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Mar 26, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MAPT-Related Spectrum Disorders

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.

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