rs3785880

Variant names:

• chr17-45916010-T-G
• rs3785880
• NM_001377265.1:c.-18+21324T>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.-18+21324T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 152,026 control chromosomes in the GnomAD database, including 13,126 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 0.40 (13126 hom., cov: 32)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.862
• Publications: 20 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.-18+21324T>G		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+21324T>G		intron_variant	Intron 1 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61080 AN: 151908 Hom.: 13111 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.402 AC: 61119 AN: 152026 Hom.: 13126 Cov.: 32 AF XY: 0.413 AC XY: 30677 AN XY: 74300

African (AFR) AF: 0.253 AC: 10506 AN: 41494

American (AMR) AF: 0.452 AC: 6917 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1437 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1970 AN: 5148

South Asian (SAS) AF: 0.496 AC: 2382 AN: 4806

European-Finnish (FIN) AF: 0.597 AC: 6312 AN: 10572

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.444 AC: 30154 AN: 67928

Other (OTH) AF: 0.397 AC: 839 AN: 2112

Alfa AF: 0.441 Hom.: 13391

Bravo AF: 0.383

Asia WGS AF: 0.417 AC: 1453 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.74
PhyloP100		-0.86
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: rs3785880; hg19: chr17-43993376;