17-45962384-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001377265.1(MAPT):c.47G>T(p.Gly16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MAPT NM_001377265.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.0130

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0983122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPT	NM_001377265.1	c.47G>T	p.Gly16Val	missense_variant	2/13	ENST00000262410.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPT	ENST00000262410.10	c.47G>T	p.Gly16Val	missense_variant	2/13	1	NM_001377265.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251108 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135734

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460410 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 11, 2019	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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MAPT-related conditions. ClinVar contains an entry for this variant (Variation ID: 548576). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces glycine with valine at codon 16 of the MAPT protein (p.Gly16Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Parkinson disease, late-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Pick disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Progressive supranuclear ophthalmoplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	4.3
Dann	Benign	0.96
DEOGEN2	Benign	0.32	T;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;.;.;.;.;.
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.29	N;N;N;N;N;N;N;N;N;.;.;.
REVEL	Benign	0.063
Sift	Benign	0.12	T;T;T;T;D;D;D;D;T;.;.;.
Sift4G	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;D;.;B;B;B;B;D;D;D;.
Vest4		0.33
MutPred		0.24		Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);Loss of catalytic residue at A15 (P = 0.0601);
MVP		0.76
MPC		0.63
ClinPred		0.26	T
GERP RS		-2.4
Varity_R		0.092
gMVP		0.018

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: rs755131800; hg19: chr17-44039750;