rs754593

Variant names:

• chr17-45977330-G-A
• rs754593
• NM_001377265.1:c.221-1045G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-45977330-G-A
• chr17-45977330-G-C
• chr17-45977330-G-T

Variant summary

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

The NM_001377265.1(MAPT):​c.221-1045G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,126 control chromosomes in the GnomAD database, including 22,639 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 0.53 (22631 hom., cov: 32)
  • Exomes 𝑓: 0.54 (8 hom.)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.245
• Publications: 30 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.221-1045G>A		intron_variant	Intron 3 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.221-1045G>A		intron_variant	Intron 3 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80367 AN: 151960 Hom.: 22614 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.499

GnomAD4 exome AF: 0.542 AC: 26 AN: 48 Hom.: 8 Cov.: 0 AF XY: 0.575 AC XY: 23 AN XY: 40

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.568 AC: 25 AN: 44

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.529 AC: 80435 AN: 152078 Hom.: 22631 Cov.: 32 AF XY: 0.537 AC XY: 39917 AN XY: 74354

African (AFR) AF: 0.329 AC: 13650 AN: 41466

American (AMR) AF: 0.589 AC: 9013 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 1999 AN: 3466

East Asian (EAS) AF: 0.795 AC: 4102 AN: 5158

South Asian (SAS) AF: 0.593 AC: 2855 AN: 4818

European-Finnish (FIN) AF: 0.670 AC: 7096 AN: 10584

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.590 AC: 40092 AN: 67980

Other (OTH) AF: 0.504 AC: 1063 AN: 2110

Alfa AF: 0.573 Hom.: 44487

Bravo AF: 0.516

Asia WGS AF: 0.695 AC: 2410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.3
DANN	Benign	0.62
PhyloP100		-0.24
Mutation Taster		=300/0	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: rs754593; hg19: chr17-44054696;