6-170568356-A-G

Variant names:

• chr6-170568356-A-G
• rs13207114
• NM_003194.5:c.678-1256A>G

Variant summary

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

The NM_003194.5(TBP):​c.678-1256A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 152,018 control chromosomes in the GnomAD database, including 11,690 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 0.38 (11690 hom., cov: 32)
• Consequence: TBP NM_003194.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.211
• Publications: 14 publications found

Genes affected

TBP (HGNC:11588): (TATA-box binding protein) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes TBP, the TATA-binding protein. A distinctive feature of TBP is a long string of glutamines in the N-terminus. This region of the protein modulates the DNA binding activity of the C terminus, and modulation of DNA binding affects the rate of transcription complex formation and initiation of transcription. The number of CAG repeats encoding the polyglutamine tract is usually 25-42, and expansion of the number of repeats to 45-66 increases the length of the polyglutamine string and is associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2016]

TBP Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 17

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.678-1256A>G		intron_variant	Intron 5 of 7	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.618-1256A>G		intron_variant	Intron 4 of 6		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.678-1256A>G		intron_variant	Intron 5 of 7	1	NM_003194.5	ENSP00000375942.2
TBP	ENST00000230354.10	c.678-1256A>G		intron_variant	Intron 5 of 7	1		ENSP00000230354.5
TBP	ENST00000540980.5	c.618-1256A>G		intron_variant	Intron 4 of 6	2		ENSP00000442132.1
TBP	ENST00000636632.1	n.*210+851A>G		intron_variant	Intron 5 of 7	5		ENSP00000490461.1

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57666 AN: 151900 Hom.: 11673 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.389

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

GnomAD4 genome AF: 0.380 AC: 57721 AN: 152018 Hom.: 11690 Cov.: 32 AF XY: 0.384 AC XY: 28541 AN XY: 74312

African (AFR) AF: 0.280 AC: 11610 AN: 41426

American (AMR) AF: 0.366 AC: 5587 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3468

East Asian (EAS) AF: 0.772 AC: 3995 AN: 5176

South Asian (SAS) AF: 0.416 AC: 2007 AN: 4822

European-Finnish (FIN) AF: 0.438 AC: 4625 AN: 10570

Middle Eastern (MID) AF: 0.329 AC: 96 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27301 AN: 67966

Other (OTH) AF: 0.392 AC: 828 AN: 2112

Alfa AF: 0.394 Hom.: 8209

Bravo AF: 0.378

Asia WGS AF: 0.564 AC: 1959 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.0
DANN	Benign	0.31
PhyloP100		0.21
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: rs13207114; hg19: chr6-170877444;