rs1052553

Positions:

• chr17-45996523-A-G

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.1857A>G​(p.Ala619=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,600,658 control chromosomes in the GnomAD database, including 32,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2153 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30776 hom.)
• Consequence: MAPT NM_001377265.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -3.43

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=-0.85).
• BP6: Variant 17-45996523-A-G is Benign according to our data. Variant chr17-45996523-A-G is described in ClinVar as [Benign]. Clinvar id is 98207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45996523-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.1857A>G	p.Ala619=	synonymous_variant	9/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1857A>G	p.Ala619=	synonymous_variant	9/13	1	NM_001377265.1	ENSP00000262410	A2

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22120 AN: 150680 Hom.: 2155 Cov.: 31

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.00160

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0667

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.145 AC: 35916 AN: 248312 Hom.: 3452 AF XY: 0.148 AC XY: 19960 AN XY: 134616

Gnomad AFR exome AF: 0.0482

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000655

Gnomad SAS exome AF: 0.0760

Gnomad FIN exome AF: 0.0678

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.196 AC: 283520 AN: 1449850 Hom.: 30776 Cov.: 53 AF XY: 0.193 AC XY: 139237 AN XY: 721366

Gnomad4 AFR exome AF: 0.0444

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.000898

Gnomad4 SAS exome AF: 0.0797

Gnomad4 FIN exome AF: 0.0797

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.179

GnomAD4 genome AF: 0.147 AC: 22110 AN: 150808 Hom.: 2153 Cov.: 31 AF XY: 0.138 AC XY: 10132 AN XY: 73648

Gnomad4 AFR AF: 0.0503

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.00161

Gnomad4 SAS AF: 0.0752

Gnomad4 FIN AF: 0.0667

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.183

Alfa AF: 0.203 Hom.: 3777

Bravo AF: 0.151

Asia WGS AF: 0.0320 AC: 112 AN: 3478

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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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, Academic 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 13, 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	-0.85
CADD	Benign	0.66
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: rs1052553; hg19: chr17-44073889;