17-45961999-C-T

Variant names:

• chr17-45961999-C-T
• rs242554
• NM_001377265.1:c.-17-322C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001377265.1(MAPT):​c.-17-322C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 151,904 control chromosomes in the GnomAD database, including 10,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (10831 hom., cov: 31)
• Consequence: MAPT NM_001377265.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.70
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 17-45961999-C-T is Benign according to our data. Variant chr17-45961999-C-T is described in ClinVar as [Benign]. Clinvar id is 1259075.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPT	NM_001377265.1	c.-17-322C>T		intron_variant	Intron 1 of 12	ENST00000262410.10	NP_001364194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPT	ENST00000262410.10	c.-17-322C>T		intron_variant	Intron 1 of 12	1	NM_001377265.1	ENSP00000262410.6

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52386 AN: 151788 Hom.: 10829 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.347

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.345 AC: 52401 AN: 151904 Hom.: 10831 Cov.: 31 AF XY: 0.349 AC XY: 25943 AN XY: 74240

African (AFR) AF: 0.108 AC: 4456 AN: 41432

American (AMR) AF: 0.397 AC: 6066 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1591 AN: 3470

East Asian (EAS) AF: 0.617 AC: 3174 AN: 5144

South Asian (SAS) AF: 0.496 AC: 2380 AN: 4802

European-Finnish (FIN) AF: 0.442 AC: 4660 AN: 10536

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29085 AN: 67936

Other (OTH) AF: 0.352 AC: 741 AN: 2108

Alfa AF: 0.723 Hom.: 12935

Bravo AF: 0.331

Asia WGS AF: 0.551 AC: 1912 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.28
DANN	Benign	0.37
PhyloP100		-1.7
PromoterAI		0.010	Neutral
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: rs242554; hg19: chr17-44039365;