chr6-170561958-ACAGCAGCAGCAG-A

Variant names:

• chr6-170561958-ACAGCAGCAGCAG-A
• rs752404282
• NM_003194.5:c.270_281delGCAGCAGCAGCA

Variant summary

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

The NM_003194.5(TBP):​c.270_281delGCAGCAGCAGCA​(p.Gln91_Gln94del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000279 in 143,470 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 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 0.00028 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00095 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• 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 40 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.270_281delGCAGCAGCAGCA	p.Gln91_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.210_221delGCAGCAGCAGCA	p.Gln71_Gln74del	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.270_281delGCAGCAGCAGCA	p.Gln91_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.270_281delGCAGCAGCAGCA	p.Gln91_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.270_281delGCAGCAGCAGCA	p.Gln91_Gln94del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 34 AN: 143364 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00130

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000204

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000954 AC: 1203 AN: 1261288 Hom.: 8 AF XY: 0.000926 AC XY: 584 AN XY: 630478

African (AFR) AF: 0.00250 AC: 72 AN: 28758

American (AMR) AF: 0.000597 AC: 25 AN: 41876

Ashkenazi Jewish (ASJ) AF: 0.000590 AC: 14 AN: 23722

East Asian (EAS) AF: 0.000156 AC: 6 AN: 38398

South Asian (SAS) AF: 0.00203 AC: 166 AN: 81714

European-Finnish (FIN) AF: 0.000301 AC: 14 AN: 46464

Middle Eastern (MID) AF: 0.00121 AC: 6 AN: 4954

European-Non Finnish (NFE) AF: 0.000904 AC: 851 AN: 941516

Other (OTH) AF: 0.000909 AC: 49 AN: 53886

GnomAD4 genome AF: 0.000279 AC: 40 AN: 143470 Hom.: 0 Cov.: 21 AF XY: 0.000357 AC XY: 25 AN XY: 70060

African (AFR) AF: 0.000510 AC: 20 AN: 39240

American (AMR) AF: 0.00 AC: 0 AN: 14656

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4916

South Asian (SAS) AF: 0.00130 AC: 6 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: 0.000204 AC: 13 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		5.0
Mutation Taster		=170/30	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs752404282; hg19: chr6-170871046; COSMIC: COSV105853242;