17-46010405-G-C

Variant names:

• chr17-46010405-G-C
• rs63750013
• NM_001377265.1:c.2091+3G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001377265.1(MAPT):​c.2091+3G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000708 in 1,411,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAPT NM_001377265.1 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33
• Publications: 5 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):

• Pick disease

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

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

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.2091+3G>C		splice_region intron	N/A	NP_001364194.1
	MAPT	NM_001123066.4		c.1920+3G>C		splice_region intron	N/A	NP_001116538.2
	MAPT	NM_016835.5		c.1866+3G>C		splice_region intron	N/A	NP_058519.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.2091+3G>C		splice_region intron	N/A	ENSP00000262410.6
	MAPT	ENST00000344290.10	TSL:1	c.1801-3838G>C		intron	N/A	ENSP00000340820.6
	MAPT	ENST00000351559.10	TSL:1	c.915+3G>C		splice_region intron	N/A	ENSP00000303214.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000564 AC: 1 AN: 177170 AF XY: 0.0000107

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1411796 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 697870

African (AFR) AF: 0.00 AC: 0 AN: 32634

American (AMR) AF: 0.00 AC: 0 AN: 37584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25296

East Asian (EAS) AF: 0.00 AC: 0 AN: 37852

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083636

Other (OTH) AF: 0.00 AC: 0 AN: 58558

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Benign	0.97
PhyloP100		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63750013; hg19: chr17-44087771;