rs63751392

chr17-46010370-GATA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_001377265.1(MAPT):c.2063_2065del(p.Asn688del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 8.72

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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001377265.1
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001377265.1. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-46010370-GATA-G is Pathogenic according to our data. Variant chr17-46010370-GATA-G is described in ClinVar as [Pathogenic]. Clinvar id is 98243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-46010370-GATA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.2063_2065del	p.Asn688del	inframe_deletion	10/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2063_2065del	p.Asn688del	inframe_deletion	10/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Progressive supranuclear palsy-parkinsonism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

Parkinson disease, late-onset Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

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: rs63751392; hg19: chr17-44087736;