17-45962351-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_001377265.1(MAPT):c.14G>T(p.Arg5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.91

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-45962351-G-A is described in Lovd as [Pathogenic].
• PP5: Variant 17-45962351-G-T is Pathogenic according to our data. Variant chr17-45962351-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14263.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-45962351-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.14G>T	p.Arg5Leu	missense_variant	2/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.14G>T	p.Arg5Leu	missense_variant	2/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459828 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Supranuclear palsy, progressive, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 13, 2017

- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	0.64	D;D;D;D;D;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;N;N;D;N;N;N;N;N;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.;.;.
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;.;D;D;D;D;D;D;D;.
Vest4		0.59
MutPred		0.29		Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);
MVP		0.77
MPC		0.73
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.15
gMVP		0.23

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: rs63750959; hg19: chr17-44039717;