17-45977067-A-G

Variant names:

• chr17-45977067-A-G
• rs3785883
• NM_001377265.1:c.221-1308A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377265.1(MAPT):​c.221-1308A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.81 in 153,306 control chromosomes in the GnomAD database, including 50,411 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50090 hom., cov: 34)
  • Exomes 𝑓: 0.78 (321 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 64 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

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.221-1308A>G		intron	N/A	NP_001364194.1
	MAPT	NM_001123066.4		c.308-1308A>G		intron	N/A	NP_001116538.2
	MAPT	NM_016835.5		c.308-1308A>G		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.221-1308A>G		intron	N/A	ENSP00000262410.6
	MAPT	ENST00000344290.10	TSL:1	c.221-1308A>G		intron	N/A	ENSP00000340820.6
	MAPT	ENST00000351559.10	TSL:1	c.308-1308A>G		intron	N/A	ENSP00000303214.7

Frequencies

GnomAD3 genomes AF: 0.810 AC: 123294 AN: 152134 Hom.: 50057 Cov.: 34

Gnomad AFR AF: 0.819

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.780

GnomAD4 exome AF: 0.781 AC: 823 AN: 1054 Hom.: 321 Cov.: 0 AF XY: 0.796 AC XY: 436 AN XY: 548

African (AFR) AF: 0.800 AC: 16 AN: 20

American (AMR) AF: 0.857 AC: 12 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.846 AC: 22 AN: 26

East Asian (EAS) AF: 0.709 AC: 112 AN: 158

South Asian (SAS) AF: 0.583 AC: 7 AN: 12

European-Finnish (FIN) AF: 0.800 AC: 88 AN: 110

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.797 AC: 523 AN: 656

Other (OTH) AF: 0.732 AC: 41 AN: 56

GnomAD4 genome AF: 0.810 AC: 123384 AN: 152252 Hom.: 50090 Cov.: 34 AF XY: 0.806 AC XY: 60019 AN XY: 74426

African (AFR) AF: 0.818 AC: 33993 AN: 41540

American (AMR) AF: 0.814 AC: 12465 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 2895 AN: 3470

East Asian (EAS) AF: 0.819 AC: 4241 AN: 5180

South Asian (SAS) AF: 0.682 AC: 3290 AN: 4826

European-Finnish (FIN) AF: 0.779 AC: 8254 AN: 10594

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.819 AC: 55700 AN: 68020

Other (OTH) AF: 0.781 AC: 1649 AN: 2112

Alfa AF: 0.817 Hom.: 199302

Bravo AF: 0.816

Asia WGS AF: 0.764 AC: 2655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.0
DANN	Benign	0.65
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs3785883; hg19: chr17-44054433;