17-45962351-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM5PP5BP4BS1_Supporting

The NM_001377265.1(MAPT):c.14G>A(p.Arg5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,611,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 2.91

Publications

86 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):

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

MAPT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-45962351-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14263.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 17-45962351-G-A is Pathogenic according to our data. Variant chr17-45962351-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14261.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.07977325). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000329 (5/152102) while in subpopulation EAS AF = 0.000968 (5/5166). AF 95% confidence interval is 0.000381. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1 link	c.14G>A	p.Arg5His	missense_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 link	c.14G>A	p.Arg5His	missense_variant	Exon 2 of 13	1	NM_001377265.1	ENSP00000262410.6		A0A7I2PJZ2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000598

AC:

AN:

250966

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1459828

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.0000224

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000605

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4314

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111792

Other (OTH)

AF:

0.0000332

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41482

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000968

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000942

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Frontotemporal dementia

Pathogenic:2

Apr 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5 of the MAPT protein (p.Arg5His). This variant is present in population databases (rs63750959, gnomAD 0.06%). This missense change has been observed in individuals with MAPT-related conditions (PMID: 11921059, 22312439, 26200045, 26601740, 28462717, 28923025, 33580635). ClinVar contains an entry for this variant (Variation ID: 14261). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects MAPT function (PMID: 11921059). This variant disrupts the p.Arg5 amino acid residue in MAPT. Other variant(s) that disrupt this residue have been observed in individuals with MAPT-related conditions (PMID: 12325083, 34305575), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:1

Jan 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with frontotemporal lobar degeneration and dementia in published literature (PMID: 11921059, 22312439, 28923025, 33580635); Did not segregate with disease in one family in published literature (PMID: 22312439); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28462717, 26200045, 11921059, 30788857, 22312439, 28923025, 33580635, Leverenz_2011_Abstract, 30279455) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;.;.;.;.;.;.;.;.;T;.;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

D;D;D;D;D;D;D;.;.;.;.;.

M_CAP

Uncertain

0.086

MetaRNN

Benign

0.080

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.8

L;L;L;L;L;L;L;L;L;L;L;L

PhyloP100

2.9

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.98

N;N;N;N;N;N;N;N;N;.;.;.

REVEL

Benign

0.19

Sift

Benign

0.17

T;T;T;T;T;D;D;T;T;.;.;.

Sift4G

Benign

0.22

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.94

P;P;P;.;D;D;D;D;P;P;P;.

Vest4

0.30

MVP

0.89

MPC

0.73

ClinPred

0.30

GERP RS

4.2

PromoterAI

0.015

Neutral

(source)

Varity_R

0.046

gMVP

0.15

Mutation Taster

=0/100

disease causing

(source)

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

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17-45962351-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over