rs1052551

Positions:

• chr17-45991558-G-A
• chr17-45991558-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377265.1(MAPT):​c.1704G>A​(p.Pro568Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,892 control chromosomes in the GnomAD database, including 32,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2121 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30642 hom.)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -2.84

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-45991558-G-A is Benign according to our data. Variant chr17-45991558-G-A is described in ClinVar as [Benign]. Clinvar id is 98204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45991558-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.1704G>A	p.Pro568Pro	synonymous_variant	8/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1704G>A	p.Pro568Pro	synonymous_variant	8/13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21640 AN: 152022 Hom.: 2123 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0738

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.145 AC: 36413 AN: 251260 Hom.: 3541 AF XY: 0.149 AC XY: 20175 AN XY: 135846

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0760

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.193 AC: 282608 AN: 1461752 Hom.: 30642 Cov.: 35 AF XY: 0.191 AC XY: 138832 AN XY: 727176

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0795

Gnomad4 FIN exome AF: 0.0724

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.142 AC: 21627 AN: 152140 Hom.: 2121 Cov.: 32 AF XY: 0.133 AC XY: 9889 AN XY: 74376

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0738

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.178

Alfa AF: 0.195 Hom.: 3601

Bravo AF: 0.147

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 25, 2011	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

MAPT-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Frontotemporal dementia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.87
DANN	Benign	0.61

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: rs1052551; hg19: chr17-44068924;