rs17652121

Positions:

• chr17-45996607-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001377265.1(MAPT):​c.1941T>C​(p.Asn647=) 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 1,613,412 control chromosomes in the GnomAD database, including 32,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2148 hom., cov: 32)
  • Exomes 𝑓: 0.19 (30650 hom.)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.0740

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-45996607-T-C is Benign according to our data. Variant chr17-45996607-T-C is described in ClinVar as [Benign]. Clinvar id is 98209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45996607-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.074 with no splicing effect.
• 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	UniProt
MAPT	NM_001377265.1	c.1941T>C	p.Asn647=	synonymous_variant	9/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.1941T>C	p.Asn647=	synonymous_variant	9/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22053 AN: 151688 Hom.: 2150 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0731

Gnomad FIN AF: 0.0652

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.187

GnomAD3 exomes AF: 0.145 AC: 36129 AN: 249222 Hom.: 3483 AF XY: 0.149 AC XY: 20035 AN XY: 134912

Gnomad AFR exome AF: 0.0472

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000653

Gnomad SAS exome AF: 0.0760

Gnomad FIN exome AF: 0.0680

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.194 AC: 282944 AN: 1461610 Hom.: 30650 Cov.: 53 AF XY: 0.191 AC XY: 138962 AN XY: 727102

Gnomad4 AFR exome AF: 0.0429

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.0724

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.145 AC: 22043 AN: 151802 Hom.: 2148 Cov.: 32 AF XY: 0.136 AC XY: 10110 AN XY: 74194

Gnomad4 AFR AF: 0.0492

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0732

Gnomad4 FIN AF: 0.0652

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.184

Alfa AF: 0.204 Hom.: 4722

Bravo AF: 0.150

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2018	- -
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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.9
DANN	Benign	0.59

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: rs17652121; hg19: chr17-44073973;