rs16940806

Variant names:

• chr17-46026460-G-A
• rs16940806
• NM_001377265.1:c.*2289G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001377265.1(MAPT):​c.*2289G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,180 control chromosomes in the GnomAD database, including 2,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2109 hom., cov: 32)
  • Exomes 𝑓: 0.079 (0 hom.)
• Consequence: MAPT NM_001377265.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.186
• Publications: 29 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-46026460-G-A is Benign according to our data. Variant chr17-46026460-G-A is described in ClinVar as Benign. ClinVar VariationId is 323696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.*2289G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.*2289G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_001377265.1	ENSP00000262410.6
MAPT	ENST00000351559.10	c.*2289G>A		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000303214.7
MAPT	ENST00000446361.7	c.*2289G>A		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000408975.3

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21757 AN: 151986 Hom.: 2111 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.0789 AC: 6 AN: 76 Hom.: 0 Cov.: 0 AF XY: 0.0625 AC XY: 3 AN XY: 48

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0893 AC: 5 AN: 56

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.143 AC: 21746 AN: 152104 Hom.: 2109 Cov.: 32 AF XY: 0.134 AC XY: 9949 AN XY: 74366

African (AFR) AF: 0.0428 AC: 1777 AN: 41530

American (AMR) AF: 0.175 AC: 2681 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3466

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5168

South Asian (SAS) AF: 0.0741 AC: 357 AN: 4818

European-Finnish (FIN) AF: 0.0646 AC: 685 AN: 10602

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14709 AN: 67928

Other (OTH) AF: 0.181 AC: 382 AN: 2110

Alfa AF: 0.202 Hom.: 2141

Bravo AF: 0.148

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MAPT-Related Spectrum Disorders Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.73
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs16940806; hg19: chr17-44103826;