rs63750349

Positions:

• chr17-45996638-C-G
• chr17-45996638-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The ENST00000262410.10(MAPT):​c.1972C>G​(p.Leu658Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L658L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT ENST00000262410.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.94

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 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000262410.10
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-45996638-C-G is Pathogenic according to our data. Variant chr17-45996638-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 14266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45996638-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.1972C>G	p.Leu658Val	missense_variant	9/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1972C>G	p.Leu658Val	missense_variant	9/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 14266). This missense change has been observed in individuals with frontotemporal dementia (PMID: 12509859, 22818528, 29253099, 33006106). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 266 of the MAPT protein (p.Leu266Val). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;.;.;.;.;.
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;.;.;L;.;.
MutationTaster	Benign	0.84	A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.025	D;T;D;D;T;T;T;T;D;.;.;.
Sift4G	Uncertain	0.019	D;D;D;T;D;T;T;D;D;D;D;T
Polyphen		1.0	D;P;D;.;D;P;P;D;D;D;P;.
Vest4		0.34
MutPred		0.64		Gain of methylation at K584 (P = 0.0382);.;.;.;.;.;.;.;.;Gain of methylation at K584 (P = 0.0382);.;.;
MVP		1.0
MPC		1.9
ClinPred		0.91	D
GERP RS		4.2
Varity_R		0.54
gMVP		0.82

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: rs63750349; hg19: chr17-44074004;