rs17651549

Positions:

• chr17-45983912-C-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.1333C>T​(p.Arg445Trp) 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 1,573,970 control chromosomes in the GnomAD database, including 32,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2118 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29992 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.86

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 (MetaRNN=0.001711458).
• BP6: Variant 17-45983912-C-T is Benign according to our data. Variant chr17-45983912-C-T is described in ClinVar as [Benign]. Clinvar id is 257502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45983912-C-T 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.1333C>T	p.Arg445Trp	missense_variant	5/13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1333C>T	p.Arg445Trp	missense_variant	5/13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21648 AN: 152120 Hom.: 2120 Cov.: 32

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0651

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.147 AC: 31553 AN: 214722 Hom.: 3065 AF XY: 0.151 AC XY: 17701 AN XY: 117022

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.000558

Gnomad SAS exome AF: 0.0766

Gnomad FIN exome AF: 0.0685

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.194 AC: 276314 AN: 1421732 Hom.: 29992 Cov.: 35 AF XY: 0.192 AC XY: 135321 AN XY: 704920

Gnomad4 AFR exome AF: 0.0321

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.000914

Gnomad4 SAS exome AF: 0.0795

Gnomad4 FIN exome AF: 0.0725

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.142 AC: 21635 AN: 152238 Hom.: 2118 Cov.: 32 AF XY: 0.133 AC XY: 9898 AN XY: 74432

Gnomad4 AFR AF: 0.0390

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0739

Gnomad4 FIN AF: 0.0651

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.181

Alfa AF: 0.204 Hom.: 5415

Bravo AF: 0.147

TwinsUK AF: 0.233 AC: 865

ALSPAC AF: 0.242 AC: 931

ESP6500AA AF: 0.0415 AC: 171

ESP6500EA AF: 0.216 AC: 1750

ExAC AF: 0.143 AC: 17269

Asia WGS AF: 0.0300 AC: 106 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Frontotemporal dementia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2018	This variant is associated with the following publications: (PMID: 23222517) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.;.;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;T;.;.
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;N;N;.
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.34
MPC		0.66
ClinPred		0.041	T
GERP RS		4.5
Varity_R		0.22
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17651549; hg19: chr17-44061278; COSMIC: COSV52248232; COSMIC: COSV52248232;