17-45962341-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001377265.1(MAPT):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37486094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.4G>T	p.Ala2Ser	missense_variant	2/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.4G>T	p.Ala2Ser	missense_variant	2/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Frontotemporal dementia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 18, 2022

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2 of the MAPT protein (p.Ala2Ser). This variant is not present in population databases (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: "Deleterious"; 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	0.13
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	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	Uncertain	0.49	T
PROVEAN	Benign	-0.69	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.75	P;D;D;.;D;D;D;D;D;P;D;.
Vest4		0.36
MutPred		0.17		Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);Gain of phosphorylation at A2 (P = 0.0087);
MVP		0.80
MPC		0.42
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.18
gMVP		0.073

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-44039707;