rs63750756

Positions:

• chr17-46010324-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001377265.1(MAPT):​c.2013T>G​(p.Asn671Lys) variant causes a missense change involving the alteration of a non-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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 3.03

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802
• PP5: Variant 17-46010324-T-G is Pathogenic according to our data. Variant chr17-46010324-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 14253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46010324-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.2013T>G	p.Asn671Lys	missense_variant	10/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.2013T>G	p.Asn671Lys	missense_variant	10/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MAPT: PP1:Strong, PS1, PM2, PS3:Moderate, PS4:Moderate -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Frontotemporal dementia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 279 of the MAPT protein (p.Asn279Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with frontotemporal dementia (PMID: 9789048, 10412802, 10489057, 10802785, 14568818, 22818528, 26295349, 27082848). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14253). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAPT protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551862:Progressive supranuclear ophthalmoplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;.;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;.;.;.;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;L;.
MutationTaster	Benign	0.99	A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.7	D;D;D;D;.;D;D;.;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D;D;D;.;D;D;.;.
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;P;D;D;P;D;D;D;P
Vest4		0.62
MutPred		0.77		Gain of catalytic residue at N596 (P = 0.0171);.;.;.;.;.;.;Gain of catalytic residue at N596 (P = 0.0171);.;
MVP		1.0
MPC		2.2
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.74
gMVP		0.94

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

Other links and lift over

dbSNP: rs63750756; hg19: chr17-44087690;