rs143624519
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001377265.1(MAPT):c.1630G>A(p.Ala544Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,614,188 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.
Frequency
Consequence
NM_001377265.1 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAPT | NM_001377265.1 | c.1630G>A | p.Ala544Thr | missense_variant | 8/13 | ENST00000262410.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAPT | ENST00000262410.10 | c.1630G>A | p.Ala544Thr | missense_variant | 8/13 | 1 | NM_001377265.1 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00181 AC: 276AN: 152184Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00151 AC: 380AN: 251282Hom.: 3 AF XY: 0.00154 AC XY: 209AN XY: 135872
GnomAD4 exome AF: 0.00275 AC: 4025AN: 1461886Hom.: 10 Cov.: 32 AF XY: 0.00265 AC XY: 1927AN XY: 727244
GnomAD4 genome AF: 0.00181 AC: 276AN: 152302Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119AN XY: 74464
ClinVar
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2019 | This variant is associated with the following publications: (PMID: 26916334, 29525180, 27594585, 28594853, 28334843, 23518664, 24319659, 26931569, 27776828, 26333800, 21176711, 23692670, 22312439, 23990795, 22595371, 22556362, 22906081, 30279455) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | MAPT: BP4, BS2 - |
Frontotemporal dementia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 152 of the MAPT protein (p.Ala152Thr). This variant is present in population databases (rs143624519, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Parkinson disease, frontotemporal dementia (FTD), or Alzheimer disease (AD), however this variant has also been reported in control populations. A single study found that this variant increases the risk for both FTD (OR =3.0, CI: 1.6–5.6, P= 0.0005) and AD (OR=2.3, CI: 1.3–4.2, P=0.004), but this result has not been independently replicated (PMID: 21176711, 22312439, 22556362, 22595371, 22906081, 23518664, 26333800, 33612544). It has also been observed to segregate with disease in related individuals. This variant is also known as NM_016835.4:c.1405G>A p.(Ala469Thr). ClinVar contains an entry for this variant (Variation ID: 323645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAPT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAPT function (PMID: 22556362, 26931567, 28334843). 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 26, 2024 | - - |
MAPT-Related Spectrum Disorders Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at