17-45962347-C-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting
The NM_001377265.1(MAPT):c.10C>A(p.Pro4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
MAPT
NM_001377265.1 missense
NM_001377265.1 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: 2.83
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.28411877).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000395 (6/152066) while in subpopulation AMR AF= 0.000328 (5/15264). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAPT | NM_001377265.1 | c.10C>A | p.Pro4Thr | missense_variant | 2/13 | ENST00000262410.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAPT | ENST00000262410.10 | c.10C>A | p.Pro4Thr | missense_variant | 2/13 | 1 | NM_001377265.1 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152066Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000959 AC: 14AN: 1459762Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 726174
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74272
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pick disease;C0338451:Frontotemporal dementia;C1850077:Progressive supranuclear palsy-parkinsonism syndrome;C3160718:Parkinson disease, late-onset;C4551863:Supranuclear palsy, progressive, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 08, 2021 | - - |
Frontotemporal dementia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 04, 2021 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4 of the MAPT protein (p.Pro4Thr). This variant is present in population databases (no rsID available, gnomAD no frequency). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.;.;.;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;.;.;.;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster
Benign
D;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;D;N;D;D;N;N;D;N;.;.;.
REVEL
Benign
Sift
Uncertain
D;D;D;D;D;D;D;D;D;.;.;.
Sift4G
Benign
T;D;T;D;D;T;T;D;T;T;D;D
Polyphen
D;D;D;.;D;D;D;D;D;D;D;.
Vest4
MutPred
Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);Gain of phosphorylation at P4 (P = 0.0889);
MVP
MPC
0.67
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at