dbSNP rs63751165: MAPT:p.Ser697Asn (chr17-46010401-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP5BP4

The NM_001377265.1(MAPT):c.2090G>A(p.Ser697Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S697I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAPT
NM_001377265.1 missense, splice_region

Scores

Splicing: ADA: 0.001246

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 5.06

Publications

89 publications found

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 Gene-Disease associations (from GenCC):

late-onset Parkinson disease
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Pick disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
semantic dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
supranuclear palsy, progressive, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
progressive supranuclear palsy-parkinsonism syndrome
Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

MAPT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001377265.1

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-46010401-G-A is Pathogenic according to our data. Variant chr17-46010401-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14254.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18888459). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377265.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPT	NM_001377265.1	MANE Select	c.2090G>A	p.Ser697Asn	missense splice_region	Exon 10 of 13	NP_001364194.1	A0A7I2PJZ2
MAPT	NM_001123066.4		c.1919G>A	p.Ser640Asn	missense splice_region	Exon 12 of 15	NP_001116538.2	P10636-9
MAPT	NM_016835.5		c.1865G>A	p.Ser622Asn	missense splice_region	Exon 11 of 14	NP_058519.3	P10636-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAPT	ENST00000262410.10	TSL:1 MANE Select	c.2090G>A	p.Ser697Asn	missense splice_region	Exon 10 of 13	ENSP00000262410.6	A0A7I2PJZ2
MAPT	ENST00000351559.10	TSL:1	c.914G>A	p.Ser305Asn	missense splice_region	Exon 9 of 12	ENSP00000303214.7	P10636-8
MAPT	ENST00000420682.7	TSL:1	c.827G>A	p.Ser276Asn	missense splice_region	Exon 8 of 11	ENSP00000413056.2	P10636-7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1415068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699446

African (AFR)

AF:

0.00

AC:

AN:

32746

American (AMR)

AF:

0.00

AC:

AN:

37782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25322

East Asian (EAS)

AF:

0.00

AC:

AN:

37978

South Asian (SAS)

AF:

0.00

AC:

AN:

80358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086102

Other (OTH)

AF:

0.00

AC:

AN:

58700

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Frontotemporal dementia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Benign

0.40

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.16

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.83

M_CAP

Benign

0.0048

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.2

PhyloP100

5.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.62

REVEL

Benign

0.16

Sift

Benign

0.29

Sift4G

Benign

1.0

Polyphen

0.79

Vest4

0.32

MutPred

0.67

Gain of relative solvent accessibility (P = 0.0479)

MVP

0.62

MPC

1.2

ClinPred

0.88

GERP RS

4.8

Varity_R

0.64

gMVP

0.78

Mutation Taster

=67/33

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.058

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over