rs143624519

Variant names:

• chr17-45991484-G-A
• rs143624519
• NM_001377265.1:c.1630G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-45991484-G-A
• chr17-45991484-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 15/22 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:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 1.70
• Publications: 253 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009972304).
• BP6: Variant 17-45991484-G-A is Benign according to our data. Variant chr17-45991484-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 323645.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00181 (276/152302) while in subpopulation NFE AF = 0.00304 (207/68022). AF 95% confidence interval is 0.0027. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.1630G>A	p.Ala544Thr	missense_variant	Exon 8 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.1630G>A	p.Ala544Thr	missense_variant	Exon 8 of 13	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00151 AC: 380 AN: 251282 AF XY: 0.00154

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00275 AC: 4025 AN: 1461886 Hom.: 10 Cov.: 32 AF XY: 0.00265 AC XY: 1927 AN XY: 727244

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86258

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00325 AC: 3616 AN: 1112008

Other (OTH) AF: 0.00343 AC: 207 AN: 60396

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74464

African (AFR) AF: 0.000698 AC: 29 AN: 41572

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00304 AC: 207 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00251 Hom.: 4

Bravo AF: 0.00179

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAPT: BP4, BS2 -

Mar 29, 2024

Athena Diagnostics

Significance: Likely risk allele

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to cause an increased risk of developing clinical features associated with this gene. This variant is statistically more frequent in individuals affected with frontotemporal dementia (FTD) and Alzheimer disease (AD) than in the general population and/or healthy controls (PMID: 22556362), even though its frequency in the general population is higher than would generally be expected for pathogenic variants in this gene (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) It has been reported in multiple studies that Ala152Thr is associated with a wide range of diagnoses, including frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinsonism, progressive supranuclear palsy (PSP), and others. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 26916334, 26931567, 26931569, 30590647, 28334843) -

Mar 27, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Frontotemporal dementia Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Mar 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MAPT-Related Spectrum Disorders Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L;.;.;.;.;.;L;L;.;.
PhyloP100		1.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.016
Sift	Benign	0.040	D;D;D;D;D;D;D;D;D;.;.;.
Sift4G	Benign	0.15	T;T;D;T;T;T;T;T;D;T;T;T
Polyphen		0.70	P;B;B;.;P;B;B;P;B;P;B;.
Vest4		0.11
MVP		0.63
MPC		0.21
ClinPred		0.058	T
GERP RS		3.1
Varity_R		0.057
gMVP		0.27
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs143624519; hg19: chr17-44068850; COSMIC: COSV105865288; COSMIC: COSV105865288;