rs63750869

Variant names:

• chr17-46018707-G-A
• rs63750869
• NM_001377265.1:c.2263G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP5 BP4 BS1_Supporting

The NM_001377265.1(MAPT):​c.2263G>A​(p.Val755Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,842 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 O:1
• Conservation: PhyloP100: 2.22
• Publications: 47 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001377265.1
• PP5: Variant 17-46018707-G-A is Pathogenic according to our data. Variant chr17-46018707-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 98231.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38086602). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000233 (34/1461630) while in subpopulation MID AF = 0.000347 (2/5768). AF 95% confidence interval is 0.0000609. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377265.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	NM_001377265.1	MANE Select	c.2263G>A	p.Val755Ile	missense	Exon 12 of 13	NP_001364194.1
	MAPT	NM_001123066.4		c.2092G>A	p.Val698Ile	missense	Exon 14 of 15	NP_001116538.2
	MAPT	NM_016835.5		c.2038G>A	p.Val680Ile	missense	Exon 13 of 14	NP_058519.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPT	ENST00000262410.10	TSL:1 MANE Select	c.2263G>A	p.Val755Ile	missense	Exon 12 of 13	ENSP00000262410.6
	MAPT	ENST00000344290.10	TSL:1	c.1972G>A	p.Val658Ile	missense	Exon 10 of 11	ENSP00000340820.6
	MAPT	ENST00000351559.10	TSL:1	c.1087G>A	p.Val363Ile	missense	Exon 11 of 12	ENSP00000303214.7

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152212 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251490 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461630 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727150

African (AFR) AF: 0.0000896 AC: 3 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111776

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152212 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

African (AFR) AF: 0.0000724 AC: 3 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000538 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1 Other:1

Sep 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21343707, 20598713, 29936232, 34999006, 31404212, 24018212, 31653695, 23047372, 37304025, 34158384, 17712160, 37070053, 35896380)

Jul 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM5, PS3, PS4_moderate

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Aug 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAPT-related disorder Pathogenic:1 Uncertain:1

Feb 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MAPT c.2092G>A variant is predicted to result in the amino acid substitution p.Val698Ile. This variant, also described as p.Val363Ile, has been reported in individuals with tauopathy spectrum disorders (Munoz et al. 2007. PubMed ID: 17712160; Rossi et al. 2013. PubMed ID: 24018212; Bessi et al. 2010. PubMed ID: 20598713; Ahmed et al. 2019. PubMed ID: 31404212; Parmera et al. 2023. PubMed ID: 37070053 ). While immunohistochemistry revealed abnormal tau staining and neuropathologic findings in patient brain tissue (Figure 2, Ahmed et al. 2019. PubMed ID: 31404212), testing for this variant in asymptomatic family members of other patients did not appear to segregate with disease, suggesting this variant may not be completely penetrant (Munoz et al. 2007. PubMed ID: 17712160; Anfossi et al. 2011. PubMed ID: 21343707; Parmera et al. 2023. PubMed ID: 37070053). Additional in vitro functional studies demonstrated that expression of this variant lead to a greater ability to promote microtubule assembly compared to wildtype (Figure 2, Rossi et al. 2014. PubMed ID: 24018212). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Although we suspect this variant may be pathogenic, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Jan 02, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAPT c.1087G>A (p.Val363Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251490 control chromosomes. c.1087G>A has been reported in the literature in multiple heterozygous individuals affected with MAPT-Related Disorders (examples: Bessi_2010, Anfossi_2011, Rossi_2013, Ahmed_2019, Parmera_2023, Internal data). These data indicate that the variant is very likely to be associated with disease. However, litearture supports that the variant may have incomplete penetrance (Anfossi_2011 and Parmera_2023). The following publications have been ascertained in the context of this evaluation (PMID: 21343707, 23047372, 20598713, 31404212, 37070053). ClinVar contains an entry for this variant (Variation ID: 98231). Based on the evidence outlined above, the variant was classified as pathogenic.

Frontotemporal dementia Pathogenic:1

Jul 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val363 amino acid residue in MAPT. Other variant(s) that disrupt this residue have been observed in individuals with MAPT-related conditions (PMID: 24018212), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects MAPT function (PMID: 24018212). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 98231). This missense change has been observed in individuals with clinical features of MAPT-related conditions (PMID: 20598713, 21343707, 23047372, 31404212; Invitae). This variant is present in population databases (rs63750869, gnomAD 0.008%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 363 of the MAPT protein (p.Val363Ile).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.036
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.58
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Polyphen		0.89	P
Vest4		0.23
MutPred		0.67		Gain of catalytic residue at V680 (P = 0.1713)
MVP		0.90
MPC		0.76
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.24
gMVP		0.86
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs63750869; hg19: chr17-44096073; COSMIC: COSV52247230;