rs63750512

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1PP3PP5_Very_Strong

The NM_001377265.1(MAPT):c.2341G>A(p.Gly781Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 13 ACMG points.

PS1

Transcript NM_001377265.1 (MAPT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

PP5

Variant 17-46024010-G-A is Pathogenic according to our data. Variant chr17-46024010-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46024010-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.2341G>A	p.Gly781Arg	missense_variant	13/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 link	c.2341G>A	p.Gly781Arg	missense_variant	13/13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251208

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000454

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pick disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2000

- -

Frontotemporal dementia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2021

This variant is present in population databases (rs63750512, ExAC 0.003%). This sequence change replaces glycine with arginine at codon 389 of the MAPT protein (p.Gly389Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant has been observed in individual(s) with frontotemporal dementia (PMID: 11117542, 27802239, 18067537, 30090657). ClinVar contains an entry for this variant (Variation ID: 14255). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects MAPT protein function (PMID: 23043292, 11117542). -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.80

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

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

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

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.8

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.8

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

REVEL

Uncertain

0.53

Sift

Uncertain

0.0080

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

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

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

Vest4

0.73

MutPred

0.61

Loss of ubiquitination at K702 (P = 0.0303);.;.;.;.;.;.;.;.;Loss of ubiquitination at K702 (P = 0.0303);.;.;

MVP

0.90

MPC

2.2

ClinPred

0.99

GERP RS

4.4

Varity_R

0.53

gMVP

0.97

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