NM_001377265.1:c.2063_2065delATA

Variant names:

• chr17-46010370-GATA-G
• rs63751392
• NM_001377265.1:c.2063_2065delATA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_001377265.1(MAPT):​c.2063_2065delATA​(p.Asn688del) variant causes a disruptive 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 (★). Synonymous variant affecting the same amino acid position (i.e. N688N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:2
• Conservation: PhyloP100: 8.72
• Publications: 25 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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 VariationId is 98243.Status of the report is criteria_provided_single_submitter, 1 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.2063_2065delATA	p.Asn688del	disruptive_inframe_deletion	Exon 10 of 13	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.1892_1894delATA	p.Asn631del	disruptive_inframe_deletion	Exon 12 of 15	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.1838_1840delATA	p.Asn613del	disruptive_inframe_deletion	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.2063_2065delATA	p.Asn688del	disruptive_inframe_deletion	Exon 10 of 13	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000351559.10	TSL:1	c.887_889delATA	p.Asn296del	disruptive_inframe_deletion	Exon 9 of 12	ENSP00000303214.7	P10636-8
	MAPT	ENST00000420682.7	TSL:1	c.800_802delATA	p.Asn267del	disruptive_inframe_deletion	Exon 8 of 11	ENSP00000413056.2	P10636-7

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (2)
1	-	-	Progressive supranuclear palsy-parkinsonism syndrome (1)
-	-	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=4/96	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: rs63751392; hg19: chr17-44087736;