6-170561958-A-ACAGCAGCAGCAGCAG

Variant names:

• chr6-170561958-A-ACAGCAGCAGCAGCAG
• rs752404282
• NM_003194.5:c.267_281dupGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_003194.5(TBP):​c.267_281dupGCAGCAGCAGCAGCA​(p.Gln90_Gln94dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,405,176 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BS2: High AC in GnomAd4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003194.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.267_281dupGCAGCAGCAGCAGCA	p.Gln90_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.207_221dupGCAGCAGCAGCAGCA	p.Gln70_Gln74dup	disruptive_inframe_insertion	Exon 2 of 7	NP_001165556.1	P20226-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.267_281dupGCAGCAGCAGCAGCA	p.Gln90_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.267_281dupGCAGCAGCAGCAGCA	p.Gln90_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.267_281dupGCAGCAGCAGCAGCA	p.Gln90_Gln94dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.000321 AC: 46 AN: 143372 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00101

Gnomad SAS AF: 0.00173

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000345

Gnomad OTH AF: 0.000506

GnomAD4 exome AF: 0.000143 AC: 180 AN: 1261698 Hom.: 0 Cov.: 0 AF XY: 0.000174 AC XY: 110 AN XY: 630694

African (AFR) AF: 0.0000695 AC: 2 AN: 28776

American (AMR) AF: 0.000119 AC: 5 AN: 41894

Ashkenazi Jewish (ASJ) AF: 0.000211 AC: 5 AN: 23728

East Asian (EAS) AF: 0.000781 AC: 30 AN: 38404

South Asian (SAS) AF: 0.000600 AC: 49 AN: 81728

European-Finnish (FIN) AF: 0.0000430 AC: 2 AN: 46476

Middle Eastern (MID) AF: 0.000202 AC: 1 AN: 4954

European-Non Finnish (NFE) AF: 0.0000828 AC: 78 AN: 941842

Other (OTH) AF: 0.000148 AC: 8 AN: 53896

GnomAD4 genome AF: 0.000321 AC: 46 AN: 143478 Hom.: 0 Cov.: 24 AF XY: 0.000357 AC XY: 25 AN XY: 70064

African (AFR) AF: 0.000178 AC: 7 AN: 39244

American (AMR) AF: 0.000205 AC: 3 AN: 14660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3200

East Asian (EAS) AF: 0.00102 AC: 5 AN: 4916

South Asian (SAS) AF: 0.00173 AC: 8 AN: 4628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000345 AC: 22 AN: 63756

Other (OTH) AF: 0.000501 AC: 1 AN: 1998

Alfa AF: 0.00 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=54/46	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs752404282; hg19: chr6-170871046;