17-46010389-C-T

Variant names:

• chr17-46010389-C-T
• rs63751273
• NM_001377265.1:c.2078C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001377265.1(MAPT):​c.2078C>T​(p.Pro693Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,421,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000813769: Experimental studies have shown that this missense change affects MAPT function (PMID:9641683, 11756436, 22022446, 22723997, 25592136, 26220942, 26269332, 26519432)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P693S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.38
• Publications: 3488 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000813769: Experimental studies have shown that this missense change affects MAPT function (PMID: 9641683, 11756436, 22022446, 22723997, 25592136, 26220942, 26269332, 26519432).; SCV002556557: Mouse models have shown changes in glutamate release and uptake (PMID:25319522) PMID:25319522 - Hunsberger et al 2015. Used a mouse model and measured glutamate levels, glutamate release and uptake/clearance in hippocampus with this variant. The variant resulted in 4-7 fold increase in glutamate release and decreased clearance. This correlated with memory performance in the maze task. concluded that may be a novel way that tau may mediate hyperexcitability (that preceeds alzheimers disease) PMID:25319522; SCV000614049: Studies show this variant causes aggregation of tau affecting microtubule assembly (PMID: 10100642, 10214944, 10627302, 10821687, 10932182, 11013246, 11115852, 26269332).; SCV002526518: Published functional studies showed that P301L expression disrupts interaction with the C-terminal half of MAPT and reduces the ability to bind and promote assembly of microtubules (Gunawardana et al., 2015; Hong et al., 1998).; SCV005417157: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001377265.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-46010388-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14256.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 17-46010389-C-T is Pathogenic according to our data. Variant chr17-46010389-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2078C>T	p.Pro693Leu	missense	Exon 10 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1907C>T	p.Pro636Leu	missense	Exon 12 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1853C>T	p.Pro618Leu	missense	Exon 11 of 14	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.2078C>T	p.Pro693Leu	missense	Exon 10 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000351559.10	TSL:1	c.902C>T	p.Pro301Leu	missense	Exon 9 of 12	ENSP00000303214.7	P10636-8
	MAPT	ENST00000420682.7	TSL:1	c.815C>T	p.Pro272Leu	missense	Exon 8 of 11	ENSP00000413056.2	P10636-7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000535 AC: 1 AN: 186808 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1421918 Hom.: 0 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 703076

African (AFR) AF: 0.00 AC: 0 AN: 32888

American (AMR) AF: 0.00 AC: 0 AN: 38606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.00 AC: 0 AN: 38278

South Asian (SAS) AF: 0.00 AC: 0 AN: 80822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1090516

Other (OTH) AF: 0.00 AC: 0 AN: 58964

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Frontotemporal dementia (6)
3	-	-	not provided (4)
1	-	-	MAPT-related disorder (1)
1	-	-	Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551862:Progressive supranuclear ophthalmoplegia (1)
1	-	-	Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1 (1)
1	-	-	Supranuclear palsy, progressive, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.89		Gain of catalytic residue at P618 (P = 0.024)
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63751273; hg19: chr17-44087755;