6-170561925-ACAGCAGCAGCAGCAG-ACAG

Variant names:

• chr6-170561925-ACAGCAGCAGCAG-A
• rs113202486
• NM_003194.5:c.204_215delGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_003194.5(TBP):​c.204_215delGCAGCAGCAGCA​(p.Gln69_Gln72del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.000016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 5 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5

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.204_215delGCAGCAGCAGCA	p.Gln69_Gln72del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.144_155delGCAGCAGCAGCA	p.Gln49_Gln52del	disruptive_inframe_deletion	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.204_215delGCAGCAGCAGCA	p.Gln69_Gln72del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.204_215delGCAGCAGCAGCA	p.Gln69_Gln72del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.204_215delGCAGCAGCAGCA	p.Gln69_Gln72del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.0000157 AC: 2 AN: 127368 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000398 AC: 34 AN: 853926 Hom.: 0 AF XY: 0.0000361 AC XY: 16 AN XY: 442654

African (AFR) AF: 0.00 AC: 0 AN: 18962

American (AMR) AF: 0.00 AC: 0 AN: 37648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21622

East Asian (EAS) AF: 0.00 AC: 0 AN: 34236

South Asian (SAS) AF: 0.00 AC: 0 AN: 68288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3518

European-Non Finnish (NFE) AF: 0.0000579 AC: 34 AN: 587572

Other (OTH) AF: 0.00 AC: 0 AN: 39764

GnomAD4 genome AF: 0.0000157 AC: 2 AN: 127464 Hom.: 0 Cov.: 0 AF XY: 0.0000166 AC XY: 1 AN XY: 60418

African (AFR) AF: 0.0000301 AC: 1 AN: 33254

American (AMR) AF: 0.00 AC: 0 AN: 11846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3176

East Asian (EAS) AF: 0.000246 AC: 1 AN: 4066

South Asian (SAS) AF: 0.00 AC: 0 AN: 3112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61322

Other (OTH) AF: 0.00 AC: 0 AN: 1638

Alfa AF: 0.00 Hom.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=141/59	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs113202486; hg19: chr6-170871013;