Variant chr17-45962351-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5

The NM_001377265.1(MAPT):c.14G>T(p.Arg5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 2.91

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-45962351-G-A is described in Lovd as [Pathogenic].

PP5

Variant 17-45962351-G-T is Pathogenic according to our data. Variant chr17-45962351-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14263.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-45962351-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1 linkuse as main transcript	c.14G>T	p.Arg5Leu	missense_variant	2/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10 linkuse as main transcript	c.14G>T	p.Arg5Leu	missense_variant	2/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459828

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726226

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Supranuclear palsy, progressive, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 13, 2017

- -

not provided

Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

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

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.64

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

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.8

L;L;L;L;L;L;L;L;L;L;L;L

MutationTaster

Benign

0.64

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

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.1

N;N;N;D;N;N;N;N;N;.;.;.

REVEL

Benign

0.26

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.15

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

Polyphen

1.0

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

Vest4

0.59

MutPred

0.29

Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);

MVP

0.77

MPC

0.73

ClinPred

0.95

GERP RS

4.2

Varity_R

0.15

gMVP

0.23

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