rs63751011

Positions:

• chr17-46010418-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001377265.1(MAPT):​c.2091+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 1,372,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 2.02

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.

• PP5: Variant 17-46010418-C-T is Pathogenic according to our data. Variant chr17-46010418-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 98222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-46010418-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.2091+16C>T		intron_variant		ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.2091+16C>T		intron_variant		1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000729 AC: 10 AN: 1372328 Hom.: 0 Cov.: 25 AF XY: 0.00000441 AC XY: 3 AN XY: 679568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000857

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Apr 05, 2022	This sequence change in MAPT is an intronic variant located in intron 10. This variant is absent from gnomAD v2.1 and v3.1. This variant is a common Welsh founder mutation and the most common variant in frontotemporal dementia (FTD) cases with British descent (PMID: 19365643). The variant has been reported to segregate with FTD in multiple families (PMID: 9641683). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may not impact splicing of MAPT. However, RT-PCR and mini-gene assays demonstrated that the variant increases exon 10 RNA expression expected to result in a change in the ratio of tau isoforms of three amino-acid repeats to those of four amino-acid repeats (PMID: 9641683). A transgenic mouse model of the variant also recapitulates the human phenotype and demonstrates much higher levels of four-repeat tau and the adult stage (PMID: 23680655). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PP1_Strong, PM2_Supporting, BP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 24, 2023	This sequence change falls in intron 9 of the MAPT gene. It does not directly change the encoded amino acid sequence of the MAPT protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with frontotemporal dementia (PMID: 9641683, 11708988, 11912108, 11971081, 17923640, 19365643, 19766248, 19786698, 20045477, 28097206). It is commonly reported in individuals of Welsh ancestry (PMID: 19365643). This variant is also known as IVS10+16C>T or 10+16C>T. ClinVar contains an entry for this variant (Variation ID: 98222). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MAPT function (PMID: 9641683, 10329720, 19914360, 23680655, 26136155). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 23, 2018	- -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2017	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2023	BP4, BP7, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 19365643, 27905268, 23885714, 10443890, 7783864, 8940276, 19914360, 26136155, 27082848, 28097206, 29253099, 29930232, 11402146, 25683866, 20045477, 19786698, 18525295, 14755449, 11708988, 11641718, 10446810, 10202939, 9392579, 9088499, 7936288, 11255441, 31031559, 31537715, 9641683, 19884572, 12847166, 15372253, 17923640, 19766248, 11971081, 11971082, 11912108, 31810826, 32804255, 31914217, 10329720, 34561610, 34158384, 37431188, 35790423, 34099697, 23680655, 27594586) -

Dementia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

MAPT-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2024

The MAPT c.1920+16C>T variant is predicted to interfere with splicing. This variant has been reported to be causative for frontotemporal dementia and results in altered splicing based on functional studies (Hutton et al. 1998. PubMed ID: 9641683; Umeda et al. 2013. PubMed ID: 23680655; Wang et al. 2010. PubMed ID: 19914360; Heutink. 2000. PubMed ID: 10767321; Sposito et al. 2015. PubMed ID: 26136155). This variant has not been reported in a large population database, indicating this variant is rare. It is consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/98222/). This variant is interpreted as pathogenic. -

Memory impairment;C0234985:Mental deterioration;C0338451:Frontotemporal dementia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Progressive supranuclear palsy-parkinsonism syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, 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). Loss of function results in the destabilization of microtubules and loss of tau-partner protein interaction. While gain of function is the increase in fibrillar and/or oligomeric aggregates and microtubules overstabilization (PMID: 26528178). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0217 - Non-coding variant with known effect. This variant affects the stability of the stem-loop structure within intron 11 resulting in aberrant splicing and increased incorporation of exon 11 (also known as exon 10 in the literature) of MAPT mRNA. The ratio of both isoforms is crucial for proper protein function (PMID: 10329720, 15950767). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are inconclusive. However, it is important to note that these tools are not optimized for variants beyond the splice region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. In an international retrospective study of frontotemporal dementia patients, this variant has been reported in 149 individuals from 48 families (PMID: 31810826). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.90

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: rs63751011; hg19: chr17-44087784;