NM_001377265.1:c.2231C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001377265.1(MAPT):​c.2231C>T​(p.Ser744Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S744S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 7.90

Publications

32 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911
PP5
Variant 17-46018675-C-T is Pathogenic according to our data. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-46018675-C-T is described in CliVar as Pathogenic. Clinvar id is 14267.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAPTNM_001377265.1 linkc.2231C>T p.Ser744Leu missense_variant Exon 12 of 13 ENST00000262410.10 NP_001364194.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAPTENST00000262410.10 linkc.2231C>T p.Ser744Leu missense_variant Exon 12 of 13 1 NM_001377265.1 ENSP00000262410.6 A0A7I2PJZ2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
31
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461874
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727242
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000270
AC:
3
AN:
1111998
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152116
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74302
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41404
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10584
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000385
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Supranuclear palsy, progressive, 1 Pathogenic:1
Nov 01, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

not provided Other:1
-
VIB Department of Molecular Genetics, University of Antwerp
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.;.;.;.;D;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;D;.;.;.;.;.
M_CAP
Pathogenic
0.57
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;.;.;.;.;.;.;.;.;H;.;.
PhyloP100
7.9
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.8
D;D;D;D;D;.;.;D;D;.;.;.
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D;D;D;D;D;.;.;D;D;.;.;.
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;P;.;D;D;D;D;P;D;D;.
Vest4
0.74
MutPred
0.73
Loss of disorder (P = 0.0143);.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0143);.;.;
MVP
1.0
MPC
1.6
ClinPred
1.0
D
GERP RS
4.9
Varity_R
0.93
gMVP
0.98
Mutation Taster
=0/100
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750425; hg19: chr17-44096041; COSMIC: COSV52241355; API