rs63750570

chr17-46018629-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001377265.1(MAPT):c.2185G>A(p.Val729Met) variant causes a missense change. 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: 31)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.18

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001377265.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 17-46018629-G-A is Pathogenic according to our data. Variant chr17-46018629-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14252.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-46018629-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.2185G>A	p.Val729Met	missense_variant	12/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2185G>A	p.Val729Met	missense_variant	12/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect MAPT protein function (PMID: 20377816, 11756496). This variant has been observed in individual(s) with frontotemporal dementia (PMID: 9629852, 28130473). It has also been observed to segregate with disease in related individuals. This variant is also known as Val279Met in the literature. ClinVar contains an entry for this variant (Variation ID: 14252). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 337 of the MAPT protein (p.Val337Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. -

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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;N;.;D;D;.;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D;D;D;.;D;D;.;.;.
Sift4G	Uncertain	0.0020	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		0.63
MutPred		0.81		Gain of ubiquitination at K657 (P = 0.14);.;.;.;.;.;.;.;.;Gain of ubiquitination at K657 (P = 0.14);.;.;
MVP		0.99
MPC		2.1
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.91

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: rs63750570; hg19: chr17-44095995;