rs63750349

Variant names:

• chr17-45996638-C-G
• rs63750349
• NM_001377265.1:c.1972C>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001377265.1(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L658P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.94
• Publications: 65 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 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 NM_001377265.1
• 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 VariationId is 14266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.1972C>G	p.Leu658Val	missense_variant	Exon 9 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1972C>G	p.Leu658Val	missense_variant	Exon 9 of 13	1	NM_001377265.1	ENSP00000262410.6

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

Sep 21, 2023

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. 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). -

Jan 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

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	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;.;.
PhyloP100		1.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750349; hg19: chr17-44074004;