NM_032538.3:c.472-376T>C

Variant names:

• chr6-43254171-T-C
• rs9462881
• NM_032538.3:c.472-376T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032538.3(TTBK1):​c.472-376T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 152,152 control chromosomes in the GnomAD database, including 19,271 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (19271 hom., cov: 33)
• Consequence: TTBK1 NM_032538.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.424
• Publications: 3 publications found

Genes affected

TTBK1 (HGNC:19140): (tau tubulin kinase 1) Summary:This gene belongs to the casein kinase 1 superfamily. The encoded protein is a neuron-specific, serine/threonine and tyrosine kinase, which regulates phosphorylation of tau, a protein that associates with microtubule assemblies and stabilizes them. Genetic variants in this gene are associated with Alzheimer's disease. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.759 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032538.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTBK1	NM_032538.3	MANE Select	c.472-376T>C		intron	N/A	NP_115927.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTBK1	ENST00000259750.9	TSL:1 MANE Select	c.472-376T>C		intron	N/A	ENSP00000259750.4
	TTBK1	ENST00000703836.1		c.472-376T>C		intron	N/A	ENSP00000515493.1
	TTBK1	ENST00000304139.6	TSL:5	n.481-376T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70960 AN: 152034 Hom.: 19218 Cov.: 33

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.379

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.439

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

GnomAD4 genome AF: 0.467 AC: 71071 AN: 152152 Hom.: 19271 Cov.: 33 AF XY: 0.463 AC XY: 34463 AN XY: 74386

African (AFR) AF: 0.766 AC: 31799 AN: 41536

American (AMR) AF: 0.367 AC: 5605 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 1163 AN: 3466

East Asian (EAS) AF: 0.415 AC: 2147 AN: 5168

South Asian (SAS) AF: 0.400 AC: 1927 AN: 4820

European-Finnish (FIN) AF: 0.353 AC: 3730 AN: 10578

Middle Eastern (MID) AF: 0.387 AC: 113 AN: 292

European-Non Finnish (NFE) AF: 0.345 AC: 23424 AN: 67986

Other (OTH) AF: 0.436 AC: 920 AN: 2112

Alfa AF: 0.387 Hom.: 20026

Bravo AF: 0.480

Asia WGS AF: 0.396 AC: 1378 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		-0.42
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: rs9462881; hg19: chr6-43221909; COSMIC: COSV52497117;