17-45954230-A-G

Variant names:

• chr17-45954230-A-G
• rs878918
• NM_001377265.1:c.-17-8091A>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.-17-8091A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,198 control chromosomes in the GnomAD database, including 5,213 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 0.23 (5213 hom., cov: 32)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• 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):

• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.412 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.-17-8091A>G		intron	N/A	NP_001364194.1	A0A7I2PJZ2
	MAPT	NM_001123066.4		c.-17-8091A>G		intron	N/A	NP_001116538.2	P10636-9
	MAPT	NM_016835.5		c.-17-8091A>G		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.-17-8091A>G		intron	N/A	ENSP00000262410.6	A0A7I2PJZ2
	MAPT	ENST00000344290.10	TSL:1	c.-17-8091A>G		intron	N/A	ENSP00000340820.6	A0A7I2PLE3
	MAPT	ENST00000351559.10	TSL:1	c.-17-8091A>G		intron	N/A	ENSP00000303214.7	P10636-8

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35749 AN: 152080 Hom.: 5220 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.229

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.235 AC: 35745 AN: 152198 Hom.: 5213 Cov.: 32 AF XY: 0.237 AC XY: 17652 AN XY: 74414

African (AFR) AF: 0.0634 AC: 2634 AN: 41550

American (AMR) AF: 0.261 AC: 3983 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1042 AN: 3472

East Asian (EAS) AF: 0.166 AC: 862 AN: 5186

South Asian (SAS) AF: 0.428 AC: 2059 AN: 4812

European-Finnish (FIN) AF: 0.265 AC: 2802 AN: 10576

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21639 AN: 67996

Other (OTH) AF: 0.229 AC: 485 AN: 2114

Alfa AF: 0.280 Hom.: 5236

Bravo AF: 0.218

Asia WGS AF: 0.269 AC: 939 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.2
DANN	Benign	0.24
PhyloP100		1.1
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: rs878918; hg19: chr17-44031596;