6-43259192-C-A

Position:

• chr6-43259192-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032538.3(TTBK1):​c.1171C>A​(p.His391Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TTBK1 NM_032538.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095125735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTBK1	NM_032538.3	c.1171C>A	p.His391Asn	missense_variant	11/15	ENST00000259750.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTBK1	ENST00000259750.9	c.1171C>A	p.His391Asn	missense_variant	11/15	1	NM_032538.3	P3
TTBK1	ENST00000703836.1	c.1171C>A	p.His391Asn	missense_variant	10/13			A2
TTBK1	ENST00000304139.6	n.1180C>A		non_coding_transcript_exon_variant	10/13	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The c.1171C>A (p.H391N) alteration is located in exon 11 (coding exon 10) of the TTBK1 gene. This alteration results from a C to A substitution at nucleotide position 1171, causing the histidine (H) at amino acid position 391 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.27	N;.
MutationTaster	Benign	0.93	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.029
Sift	Benign	0.20	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.010	B;.
Vest4		0.40
MutPred		0.31		Gain of catalytic residue at H391 (P = 0.1816);.;
MVP		0.16
MPC		0.35
ClinPred		0.31	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-43226930; COSMIC: COSV99445449;