17-45908813-G-A

Variant names:

• chr17-45908813-G-A
• rs1467967
• NM_001377265.1:c.-18+14127G>A

Variant summary

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

The NM_001377265.1(MAPT):​c.-18+14127G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 152,042 control chromosomes in the GnomAD database, including 33,310 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 0.66 (33310 hom., cov: 32)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.594
• Publications: 58 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

ENSG00000262881 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.-18+14127G>A		intron_variant	Intron 1 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.-18+14127G>A		intron_variant	Intron 1 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100360 AN: 151924 Hom.: 33263 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.684

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.667

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

GnomAD4 genome AF: 0.661 AC: 100462 AN: 152042 Hom.: 33310 Cov.: 32 AF XY: 0.657 AC XY: 48828 AN XY: 74330

African (AFR) AF: 0.677 AC: 28063 AN: 41466

American (AMR) AF: 0.678 AC: 10355 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 2374 AN: 3470

East Asian (EAS) AF: 0.406 AC: 2093 AN: 5158

South Asian (SAS) AF: 0.563 AC: 2713 AN: 4820

European-Finnish (FIN) AF: 0.648 AC: 6849 AN: 10570

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.673 AC: 45708 AN: 67966

Other (OTH) AF: 0.663 AC: 1401 AN: 2112

Alfa AF: 0.668 Hom.: 86859

Bravo AF: 0.664

Asia WGS AF: 0.477 AC: 1663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.073
DANN	Benign	0.29
PhyloP100		-0.59
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: rs1467967; hg19: chr17-43986179;