chr17-46010418-C-T

Variant names:

• chr17-46010418-C-T
• rs63751011
• NM_001377265.1:c.2091+16C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001767383: Published functional studies demonstrate that this variant leads to aberrant splicing of exon 10 (PMID:23680655, 9641683)" and additional evidence is available in ClinVar.

• 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:13 O:1
• Conservation: PhyloP100: 2.02
• Publications: 17 publications found

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]

MAPT Gene-Disease associations (from GenCC):

• late-onset Parkinson disease

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• semantic dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• supranuclear palsy, progressive, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001767383: Published functional studies demonstrate that this variant leads to aberrant splicing of exon 10 (PMID: 23680655, 9641683); SCV000815082: Experimental studies have shown that this variant affects MAPT function (PMID: 9641683, 10329720, 19914360, 23680655, 26136155).; SCV002498672: 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).; SCV004118409: 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).; SCV006086681: At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected the MAPT protein function (Umeda_2013).
• PP5: Variant 17-46010418-C-T is Pathogenic according to our data. Variant chr17-46010418-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 98222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377265.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.2091+16C>T		intron	N/A	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1920+16C>T		intron	N/A	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1866+16C>T		intron	N/A	NP_058519.3	P10636-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.2091+16C>T		intron	N/A	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.1801-3825C>T		intron	N/A	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.915+16C>T		intron	N/A	ENSP00000303214.7	P10636-8

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

African (AFR) AF: 0.00 AC: 0 AN: 31674

American (AMR) AF: 0.00 AC: 0 AN: 36584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25052

East Asian (EAS) AF: 0.00 AC: 0 AN: 37124

South Asian (SAS) AF: 0.00 AC: 0 AN: 79136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00000857 AC: 9 AN: 1050116

Other (OTH) AF: 0.0000175 AC: 1 AN: 57138

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Frontotemporal dementia (5)
3	-	-	not provided (4)
2	-	-	MAPT-related disorder (2)
1	-	-	Dementia (1)
1	-	-	Memory impairment;C0234985:Mental deterioration;C0338451:Frontotemporal dementia (1)
1	-	-	Progressive supranuclear palsy-parkinsonism syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		2.0
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63751011; hg19: chr17-44087784;