Genetic Variant NM_001377265.1:c.220+18C>T (chr17-45971963-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001377265.1(MAPT):c.220+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,601,192 control chromosomes in the GnomAD database, including 32,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2141 hom., cov: 32)

Exomes 𝑓: 0.19 ( 30553 hom. )

Consequence

MAPT
NM_001377265.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.603

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 17-45971963-C-T is Benign according to our data. Variant chr17-45971963-C-T is described in ClinVar as [Benign]. Clinvar id is 257503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-45971963-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 rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.220+18C>T		intron_variant	Intron 3 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10 link	c.220+18C>T		intron_variant	Intron 3 of 12	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22005

AN:

152060

Hom.:

2143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0477

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0740

Gnomad FIN

AF:

0.0650

Gnomad MID

AF:

0.213

Gnomad NFE

AF:

0.217

Gnomad OTH

AF:

0.185

GnomAD3 exomes

AF:

0.145

AC:

36282

AN:

249538

Hom.:

3496

AF XY:

0.149

AC XY:

20115

AN XY:

135094

show subpopulations

Gnomad AFR exome

AF:

0.0454

Gnomad AMR exome

AF:

0.119

Gnomad ASJ exome

AF:

0.254

Gnomad EAS exome

AF:

0.000654

Gnomad SAS exome

AF:

0.0761

Gnomad FIN exome

AF:

0.0681

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.194

AC:

281334

AN:

1449014

Hom.:

30553

Cov.:

AF XY:

0.192

AC XY:

138258

AN XY:

721602

show subpopulations

Gnomad4 AFR exome

AF:

0.0408

Gnomad4 AMR exome

AF:

0.125

Gnomad4 ASJ exome

AF:

0.257

Gnomad4 EAS exome

AF:

0.000908

Gnomad4 SAS exome

AF:

0.0799

Gnomad4 FIN exome

AF:

0.0724

Gnomad4 NFE exome

AF:

0.223

Gnomad4 OTH exome

AF:

0.178

GnomAD4 genome

AF:

0.145

AC:

21994

AN:

152178

Hom.:

2141

Cov.:

AF XY:

0.136

AC XY:

10085

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0476

Gnomad4 AMR

AF:

0.175

Gnomad4 ASJ

AF:

0.239

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0740

Gnomad4 FIN

AF:

0.0650

Gnomad4 NFE

AF:

0.217

Gnomad4 OTH

AF:

0.182

Alfa

AF:

0.180

Hom.:

505

Bravo

AF:

0.150

Asia WGS

AF:

0.0310

AC:

110

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Frontotemporal dementia

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.7

DANN

Benign

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over