NM_003194.5:c.273_281delGCAGCAGCA

Variant names:

• chr6-170561958-ACAGCAGCAG-A
• rs752404282
• NM_003194.5:c.273_281delGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_003194.5(TBP):​c.273_281delGCAGCAGCA​(p.Gln92_Gln94del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000411 in 143,466 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q91Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 21)
  • Exomes 𝑓: 0.0052 (451 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.47
• 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561958-ACAGCAGCAG-A is Benign according to our data. Variant chr6-170561958-ACAGCAGCAG-A is described in ClinVar as Benign. ClinVar VariationId is 599434.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 59 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.273_281delGCAGCAGCA	p.Gln92_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.213_221delGCAGCAGCA	p.Gln72_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.273_281delGCAGCAGCA	p.Gln92_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.273_281delGCAGCAGCA	p.Gln92_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.273_281delGCAGCAGCA	p.Gln92_Gln94del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.000419 AC: 60 AN: 143360 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000332

Gnomad AMI AF: 0.00123

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00203

Gnomad SAS AF: 0.000864

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000392

Gnomad OTH AF: 0.00202

GnomAD2 exomes AF: 0.00968 AC: 1449 AN: 149640 AF XY: 0.0106

Gnomad AFR exome AF: 0.00470

Gnomad AMR exome AF: 0.00733

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.0188

Gnomad FIN exome AF: 0.00726

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.00680

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00521 AC: 6567 AN: 1259378 Hom.: 451 AF XY: 0.00482 AC XY: 3036 AN XY: 629606

African (AFR) AF: 0.00139 AC: 40 AN: 28754

American (AMR) AF: 0.00347 AC: 145 AN: 41792

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 30 AN: 23716

East Asian (EAS) AF: 0.00302 AC: 116 AN: 38350

South Asian (SAS) AF: 0.00241 AC: 197 AN: 81646

European-Finnish (FIN) AF: 0.00170 AC: 79 AN: 46420

Middle Eastern (MID) AF: 0.00323 AC: 16 AN: 4946

European-Non Finnish (NFE) AF: 0.00612 AC: 5754 AN: 939922

Other (OTH) AF: 0.00353 AC: 190 AN: 53832

GnomAD4 genome AF: 0.000411 AC: 59 AN: 143466 Hom.: 1 Cov.: 21 AF XY: 0.000385 AC XY: 27 AN XY: 70060

African (AFR) AF: 0.000331 AC: 13 AN: 39238

American (AMR) AF: 0.000205 AC: 3 AN: 14658

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

East Asian (EAS) AF: 0.00203 AC: 10 AN: 4914

South Asian (SAS) AF: 0.000864 AC: 4 AN: 4628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9990

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

European-Non Finnish (NFE) AF: 0.000392 AC: 25 AN: 63756

Other (OTH) AF: 0.00150 AC: 3 AN: 1998

Alfa AF: 0.00 Hom.: 4

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=176/24	polymorphism (auto)

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: COSV57830486;