rs754593

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.221-1045G>A		intron_variant		ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.221-1045G>A		intron_variant		1	NM_001377265.1	ENSP00000262410	A2

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

Gnomad4 EAS exome AF: 0.250

Gnomad4 NFE exome AF: 0.568

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

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.577

Gnomad4 EAS AF: 0.795

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.590

Gnomad4 OTH AF: 0.504

Alfa AF: 0.579 Hom.: 18908

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs754593; hg19: chr17-44054696;