rs193920969

chr17-45983638-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377265.1(MAPT):c.1059G>C(p.Glu353Asp) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.39

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25440013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.1059G>C	p.Glu353Asp	missense_variant	5/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.1059G>C	p.Glu353Asp	missense_variant	5/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.67	T;T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.55	N;N;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;D;D;.
Sift4G	Benign	0.070	T;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.13
MutPred		0.12		Loss of catalytic residue at E278 (P = 0.1476);Loss of catalytic residue at E278 (P = 0.1476);Loss of catalytic residue at E278 (P = 0.1476);Loss of catalytic residue at E278 (P = 0.1476);
MVP		0.79
MPC		0.49
ClinPred		0.46	T
GERP RS		3.5
Varity_R		0.090
gMVP		0.13

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: rs193920969; hg19: chr17-44061004; COSMIC: COSV52244362; COSMIC: COSV52244362;