rs63750869

chr17-46018707-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

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:2 U:1 O:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 id is 98231.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1, Pathogenic=1}. Variant chr17-46018707-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.38086602).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.2263G>A	p.Val755Ile	missense_variant	12/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.2263G>A	p.Val755Ile	missense_variant	12/13	1	NM_001377265.1	A2

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

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

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 SAS 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

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

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

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 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:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2016	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Frontotemporal dementia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 20, 2022

ClinVar contains an entry for this variant (Variation ID: 98231). 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"). 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). -

MAPT-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 06, 2024

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. -

Computational scores

Source: dbNSFP v4.3

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;.;.;.;.;.;.;.;.;D;.;.
Eigen	Benign	-0.036
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.84	T;T;T;D;T;T;T;.;.;.;.;.
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.;.;.;L;.;.
MutationTaster	Benign	0.82	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.81	N;N;N;N;N;.;.;N;N;.;.;.
REVEL	Uncertain	0.58
Sift	Benign	0.12	T;T;T;T;T;.;.;T;T;.;.;.
Sift4G	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.89	P;B;B;.;B;B;B;B;B;P;B;.
Vest4		0.23
MutPred		0.67		Gain of catalytic residue at V680 (P = 0.1713);.;.;.;.;.;.;.;.;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

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

Other links and lift over

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