17-45962347-C-A

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

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.83
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=0.28411877).
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
MAPTNM_001377265.1 linkuse as main transcriptc.10C>A p.Pro4Thr missense_variant 2/13 ENST00000262410.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAPTENST00000262410.10 linkuse as main transcriptc.10C>A p.Pro4Thr missense_variant 2/131 NM_001377265.1 A2

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
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
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1459762
Hom.:
0
Cov.:
33
AF XY:
0.0000110
AC XY:
8
AN XY:
726174
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152066
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74272
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.000328
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:
0.0000847
Hom.:
0
Bravo
AF:
0.000106

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 submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 08, 2021- -
Frontotemporal dementia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 04, 2021This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.053
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;.;.;.;.;.;.;.;.;T;.;.
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;.;.;.;.;.
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
1.8
L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster
Benign
1.0
D;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.7
N;D;N;D;D;N;N;D;N;.;.;.
REVEL
Benign
0.11
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D;.;.;.
Sift4G
Benign
0.25
T;D;T;D;D;T;T;D;T;T;D;D
Polyphen
1.0
D;D;D;.;D;D;D;D;D;D;D;.
Vest4
0.45
MutPred
0.27
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
0.86
MPC
0.67
ClinPred
0.93
D
GERP RS
4.2
Varity_R
0.15
gMVP
0.19

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: rs974837695; hg19: chr17-44039713; API