rs63750711

Positions:

• chr17-46018645-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001377265.1(MAPT):​c.2201A>T​(p.Glu734Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.15

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 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
• PP5: Variant 17-46018645-A-T is Pathogenic according to our data. Variant chr17-46018645-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 14258.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018645-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.2201A>T	p.Glu734Val	missense_variant	12/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2201A>T	p.Glu734Val	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:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Frontotemporal dementia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2000

- -

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.;.;.;.;.;.;.;D;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.61	T;T;T;T;T;T;T;.;.;.;.;.
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;.;.;L;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;.;.;D;D;.;.;.
REVEL	Pathogenic	0.79
Sift	Benign	0.11	T;T;T;T;T;.;.;T;T;.;.;.
Sift4G	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.91	P;P;B;.;D;P;D;D;B;P;P;.
Vest4		0.42
MutPred		0.76		Gain of MoRF binding (P = 0.0249);.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0249);.;.;
MVP		0.96
MPC		2.0
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.95

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: rs63750711; hg19: chr17-44096011;