rs63750612

chr17-45991562-G-Achr17-45991562-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001377265.1(MAPT):c.1708G>A(p.Ala570Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,614,058 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (56 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.997

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019565523).
• BP6: Variant 17-45991562-G-A is Benign according to our data. Variant chr17-45991562-G-A is described in ClinVar as [Benign]. Clinvar id is 98205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45991562-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2152/152232) while in subpopulation AFR AF= 0.0491 (2040/41524). AF 95% confidence interval is 0.0474. There are 44 homozygotes in gnomad4. There are 1000 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.1708G>A	p.Ala570Thr	missense_variant	8/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.1708G>A	p.Ala570Thr	missense_variant	8/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2154 AN: 152114 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0493

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00364 AC: 915 AN: 251212 Hom.: 26 AF XY: 0.00264 AC XY: 359 AN XY: 135824

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00141 AC: 2061 AN: 1461826 Hom.: 56 Cov.: 33 AF XY: 0.00117 AC XY: 851 AN XY: 727212

Gnomad4 AFR exome AF: 0.0499

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.0141 AC: 2152 AN: 152232 Hom.: 44 Cov.: 32 AF XY: 0.0134 AC XY: 1000 AN XY: 74430

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00253 Hom.: 17

Bravo AF: 0.0162

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00421 AC: 511

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2018	- -

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

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.28
Dann	Benign	0.85
DEOGEN2	Benign	0.28	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;.;.;.;.;.
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.41	N;.;N;.;.;.;.;.;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.47	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.0050
Sift	Benign	0.43	T;T;T;T;T;T;T;T;T;.;.;.
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.010	B;B;B;.;B;B;B;B;B;B;B;.
Vest4		0.029
MVP		0.30
MPC		0.15
ClinPred		0.0023	T
GERP RS		-8.8
Varity_R		0.026
gMVP		0.14

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: rs63750612; hg19: chr17-44068928; COSMIC: COSV52248827; COSMIC: COSV52248827;