dbSNP rs63750635: MAPT:p.Ser712Phe (chr17-46014286-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001377265.1(MAPT):c.2135C>T(p.Ser712Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 7.91

Publications

81 publications found

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 Gene-Disease associations (from GenCC):

Pick disease
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
semantic dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
supranuclear palsy, progressive, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
late-onset Parkinson disease
Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
progressive supranuclear palsy-parkinsonism syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

MAPT links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 17-46014286-C-T is Pathogenic according to our data. Variant chr17-46014286-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.2135C>T	p.Ser712Phe	missense_variant	Exon 11 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.2135C>T	p.Ser712Phe	missense_variant	Exon 11 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000653

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pick disease

Pathogenic:1

Mar 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Frontotemporal dementia

Pathogenic:1

Jan 22, 2018

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Other:1

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

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

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.;.;.;.;.;.;.;.;M;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.5

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

0.86

MutPred

0.79

Loss of disorder (P = 0.0034);.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0034);.;.;

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over