chr17-45962368-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001377265.1(MAPT):ā€‹c.31A>Cā€‹(p.Met11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000062 ( 0 hom. )

Consequence

MAPT
NM_001377265.1 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.568
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15519252).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAPTNM_001377265.1 linkuse as main transcriptc.31A>C p.Met11Leu missense_variant 2/13 ENST00000262410.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAPTENST00000262410.10 linkuse as main transcriptc.31A>C p.Met11Leu missense_variant 2/131 NM_001377265.1 A2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152002
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251124
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1460208
Hom.:
0
Cov.:
33
AF XY:
0.00000826
AC XY:
6
AN XY:
726394
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152002
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74238
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Frontotemporal dementia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 12, 2022This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 11 of the MAPT protein (p.Met11Leu). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MAPT-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
14
DANN
Benign
0.84
DEOGEN2
Uncertain
0.44
T;.;.;.;.;.;.;.;.;T;.;.
Eigen
Benign
-0.71
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.040
N
LIST_S2
Benign
0.83
T;T;T;T;T;D;D;.;.;.;.;.
M_CAP
Benign
0.0084
T
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.73
N;N;N;N;N;N;N;N;N;.;.;.
REVEL
Benign
0.020
Sift
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;.;.;.
Sift4G
Benign
0.15
T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.015
B;P;B;.;B;B;B;B;B;B;P;.
Vest4
0.27
MutPred
0.30
Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);Loss of disorder (P = 0.1636);
MVP
0.41
MPC
0.17
ClinPred
0.21
T
GERP RS
1.3
Varity_R
0.48
gMVP
0.0073

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.

Other links and lift over

dbSNP: rs1262800598; hg19: chr17-44039734; API