rs62063787

chr17-45983670-T-C

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.1091T>C(p.Val364Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,613,954 control chromosomes in the GnomAD database, including 32,819 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 0.15 (2143 hom., cov: 33)
  • Exomes 𝑓: 0.19 (30676 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.0240

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=0.0047382116).
• BP6: Variant 17-45983670-T-C is Benign according to our data. Variant chr17-45983670-T-C is described in ClinVar as [Benign]. Clinvar id is 98200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45983670-T-C 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	UniProt
MAPT	NM_001377265.1	c.1091T>C	p.Val364Ala	missense_variant	5/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.1091T>C	p.Val364Ala	missense_variant	5/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22090 AN: 152132 Hom.: 2145 Cov.: 33

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0742

Gnomad FIN AF: 0.0649

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.146 AC: 36543 AN: 251038 Hom.: 3544 AF XY: 0.149 AC XY: 20239 AN XY: 135800

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: 0.0761

Gnomad FIN exome AF: 0.0681

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.194 AC: 283025 AN: 1461704 Hom.: 30676 Cov.: 36 AF XY: 0.191 AC XY: 139002 AN XY: 727146

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.0725

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.145 AC: 22080 AN: 152250 Hom.: 2143 Cov.: 33 AF XY: 0.136 AC XY: 10127 AN XY: 74440

Gnomad4 AFR AF: 0.0493

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0742

Gnomad4 FIN AF: 0.0649

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.183

Alfa AF: 0.205 Hom.: 5568

Bravo AF: 0.150

TwinsUK AF: 0.232 AC: 861

ALSPAC AF: 0.241 AC: 929

ESP6500AA AF: 0.0515 AC: 227

ESP6500EA AF: 0.224 AC: 1928

ExAC AF: 0.145 AC: 17579

Asia WGS AF: 0.0310 AC: 111 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 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, Academic Medical Center	-	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2018	This variant is associated with the following publications: (PMID: 23222517) -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Frontotemporal dementia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.72
Dann	Benign	0.20
DEOGEN2	Benign	0.28	T;.;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.25	T;T;.;.
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.55	N;N;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.12	N;N;N;.
REVEL	Benign	0.061
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	0.92	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.022
MPC		0.18
ClinPred		0.00087	T
GERP RS		-1.4
Varity_R		0.026
gMVP		0.083

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: rs62063787; hg19: chr17-44061036; COSMIC: COSV52237062; COSMIC: COSV52237062;