rs63750912

Positions:

• chr17-46010375-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001377265.1(MAPT):​c.2064T>C​(p.Asn688=) variant causes a synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.75

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-46010375-T-C is Pathogenic according to our data. Variant chr17-46010375-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 14257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46010375-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.2064T>C	p.Asn688=	synonymous_variant	10/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2064T>C	p.Asn688=	synonymous_variant	10/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with frontotemporal dementia, with or without parkinsonism (MIM#600274), Pick disease (MIM#172700), progressive supranuclear palsy (MIM#601104). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Interfamilial and intrafamilial phenotypic heterogeneity have been described (PMID: 23727082). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect. This synonymous variant has been shown to result in increased exon 10 inclusion (referring to the MANE transcript NM_001377265.1). This has been associated with increased expression of 4R tau isoforms, thereby disrupting the 3R:4R tau ratio which is crucial for proper functioning of tau (PMIDs: 11117553). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Multiple variants within this same intron and exon junction, such as +3, +15 and +16, have been shown to result in increased exon 10 inclusion similar to this synonymous variant (PMIDs: 11117553, 26136155, 26297556). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been regarded as likely pathogenic and pathogenic by clinical laboratories (LOVD, ClinVar) and has been detected in individuals with frontotemporal dementia (PMIDs: 11117553, 34305575) and progressive supranuclear palsy (PMID: 22818528). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.86

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: rs63750912; hg19: chr17-44087741;