rs17650901

Variant names:

• chr17-45962325-A-G
• rs17650901
• NM_001377265.1:c.-13A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-45962325-A-G
• chr17-45962325-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377265.1(MAPT):​c.-13A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,610,688 control chromosomes in the GnomAD database, including 32,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2131 hom., cov: 31)
  • Exomes 𝑓: 0.19 (30574 hom.)
• Consequence: MAPT NM_001377265.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.232
• Publications: 55 publications found

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 Gene-Disease associations (from GenCC):

• Pick disease

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• semantic dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• supranuclear palsy, progressive, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• progressive supranuclear palsy-parkinsonism syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-45962325-A-G is Benign according to our data. Variant chr17-45962325-A-G is described in ClinVar as [Benign]. Clinvar id is 257501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.-13A>G		5_prime_UTR_variant	Exon 2 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.-13A>G		5_prime_UTR_variant	Exon 2 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21781 AN: 151904 Hom.: 2133 Cov.: 31

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.145 AC: 36170 AN: 250078 AF XY: 0.148

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0676

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.193 AC: 281949 AN: 1458666 Hom.: 30574 Cov.: 33 AF XY: 0.191 AC XY: 138477 AN XY: 725612

African (AFR) AF: 0.0364 AC: 1215 AN: 33402

American (AMR) AF: 0.125 AC: 5593 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6688 AN: 26112

East Asian (EAS) AF: 0.000882 AC: 35 AN: 39700

South Asian (SAS) AF: 0.0795 AC: 6842 AN: 86096

European-Finnish (FIN) AF: 0.0723 AC: 3861 AN: 53392

Middle Eastern (MID) AF: 0.198 AC: 831 AN: 4188

European-Non Finnish (NFE) AF: 0.222 AC: 246233 AN: 1110940

Other (OTH) AF: 0.177 AC: 10651 AN: 60176

GnomAD4 genome AF: 0.143 AC: 21770 AN: 152022 Hom.: 2131 Cov.: 31 AF XY: 0.134 AC XY: 9963 AN XY: 74306

African (AFR) AF: 0.0427 AC: 1773 AN: 41484

American (AMR) AF: 0.175 AC: 2673 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5178

South Asian (SAS) AF: 0.0740 AC: 355 AN: 4800

European-Finnish (FIN) AF: 0.0648 AC: 686 AN: 10594

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14743 AN: 67944

Other (OTH) AF: 0.181 AC: 382 AN: 2106

Alfa AF: 0.194 Hom.: 2968

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Aug 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MAPT-Related Spectrum Disorders Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		0.23
PromoterAI		-0.021	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17650901; hg19: chr17-44039691;