rs63750869

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS1_Supporting

The NM_001377265.1(MAPT):c.2263G>A(p.Val755Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2O:1

Conservation

PhyloP100: 2.22

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 Likely_benign. Variant got -1 ACMG points.

PP5

Variant 17-46018707-G-A is Pathogenic according to our data. Variant chr17-46018707-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 98231.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2, not_provided=1}. Variant chr17-46018707-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.38086602). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000233 (34/1461630) while in subpopulation MID AF= 0.000347 (2/5768). AF 95% confidence interval is 0.0000609. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.2263G>A	p.Val755Ile	missense_variant	Exon 12 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.2263G>A	p.Val755Ile	missense_variant	Exon 12 of 13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251490

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461630

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1Other:1

Aug 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21343707, 20598713, 29936232, 34999006, 31404212, 24018212, 31653695, 23047372, 37304025, 34158384, 17712160, 37070053, 35896380) -

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM5, PS3, PS4_moderate -

MAPT-related disorder

Pathogenic:1Uncertain:1

Jan 02, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAPT c.1087G>A (p.Val363Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251490 control chromosomes. c.1087G>A has been reported in the literature in multiple heterozygous individuals affected with MAPT-Related Disorders (examples: Bessi_2010, Anfossi_2011, Rossi_2013, Ahmed_2019, Parmera_2023, Internal data). These data indicate that the variant is very likely to be associated with disease. However, litearture supports that the variant may have incomplete penetrance (Anfossi_2011 and Parmera_2023). The following publications have been ascertained in the context of this evaluation (PMID: 21343707, 23047372, 20598713, 31404212, 37070053). ClinVar contains an entry for this variant (Variation ID: 98231). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MAPT c.2092G>A variant is predicted to result in the amino acid substitution p.Val698Ile. This variant, also described as p.Val363Ile, has been reported in individuals with tauopathy spectrum disorders (Munoz et al. 2007. PubMed ID: 17712160; Rossi et al. 2013. PubMed ID: 24018212; Bessi et al. 2010. PubMed ID: 20598713; Ahmed et al. 2019. PubMed ID: 31404212; Parmera et al. 2023. PubMed ID: 37070053 ). While immunohistochemistry revealed abnormal tau staining and neuropathologic findings in patient brain tissue (Figure 2, Ahmed et al. 2019. PubMed ID: 31404212), testing for this variant in asymptomatic family members of other patients did not appear to segregate with disease, suggesting this variant may not be completely penetrant (Munoz et al. 2007. PubMed ID: 17712160; Anfossi et al. 2011. PubMed ID: 21343707; Parmera et al. 2023. PubMed ID: 37070053). Additional in vitro functional studies demonstrated that expression of this variant lead to a greater ability to promote microtubule assembly compared to wildtype (Figure 2, Rossi et al. 2014. PubMed ID: 24018212). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Although we suspect this variant may be pathogenic, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Frontotemporal dementia

Pathogenic:1

Jul 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val363 amino acid residue in MAPT. Other variant(s) that disrupt this residue have been observed in individuals with MAPT-related conditions (PMID: 24018212), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects MAPT function (PMID: 24018212). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 98231). This missense change has been observed in individuals with clinical features of MAPT-related conditions (PMID: 20598713, 21343707, 23047372, 31404212; Invitae). This variant is present in population databases (rs63750869, gnomAD 0.008%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 363 of the MAPT protein (p.Val363Ile). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

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

Eigen

Benign

-0.036

Eigen_PC

Benign

0.064

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.065

MetaRNN

Benign

0.38

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

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.8

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

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.81

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

REVEL

Uncertain

0.58

Sift

Benign

0.12

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

Sift4G

Benign

0.16

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

Polyphen

0.89

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

Vest4

0.23

MutPred

0.67

Gain of catalytic residue at V680 (P = 0.1713);.;.;.;.;.;.;.;.;Gain of catalytic residue at V680 (P = 0.1713);.;.;

MVP

0.90

MPC

0.76

ClinPred

0.11

GERP RS

3.9

Varity_R

0.24

gMVP

0.86

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