chr17-45962351-G-T

Variant names:

• chr17-45962351-G-T
• rs63750959
• NM_001377265.1:c.14G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 86 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 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14261.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.14G>T	p.Arg5Leu	missense_variant	Exon 2 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.14G>T	p.Arg5Leu	missense_variant	Exon 2 of 13	1	NM_001377265.1	ENSP00000262410.6

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

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4314

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60222

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Sep 13, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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
PhyloP100		2.9
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
PromoterAI		-0.00090	Neutral
Varity_R		0.15
gMVP		0.23
Mutation Taster		=0/100	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: rs63750959; hg19: chr17-44039717;