chr6-170561958-A-ACAGCAGCAG

Variant names:

• chr6-170561958-A-ACAGCAGCAG
• rs752404282
• NM_003194.5:c.273_281dupGCAGCAGCA

Variant summary

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

The NM_003194.5(TBP):​c.273_281dupGCAGCAGCA​(p.Gln92_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 0.00204 in 1,405,048 control chromosomes in the GnomAD database, including 12 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 24)
  • Exomes 𝑓: 0.0021 (10 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 263 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_281dupGCAGCAGCA	p.Gln92_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.213_221dupGCAGCAGCA	p.Gln72_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.273_281dupGCAGCAGCA	p.Gln92_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.273_281dupGCAGCAGCA	p.Gln92_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.273_281dupGCAGCAGCA	p.Gln92_Gln94dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 263 AN: 143376 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.00148

Gnomad AMI AF: 0.00245

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00625

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00583

Gnomad FIN AF: 0.00100

Gnomad MID AF: 0.00685

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000506

GnomAD4 exome AF: 0.00206 AC: 2600 AN: 1261566 Hom.: 10 Cov.: 0 AF XY: 0.00211 AC XY: 1329 AN XY: 630614

African (AFR) AF: 0.00142 AC: 41 AN: 28774

American (AMR) AF: 0.00127 AC: 53 AN: 41894

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 127 AN: 23716

East Asian (EAS) AF: 0.00286 AC: 110 AN: 38400

South Asian (SAS) AF: 0.00658 AC: 538 AN: 81710

European-Finnish (FIN) AF: 0.00123 AC: 57 AN: 46474

Middle Eastern (MID) AF: 0.00141 AC: 7 AN: 4954

European-Non Finnish (NFE) AF: 0.00162 AC: 1530 AN: 941752

Other (OTH) AF: 0.00254 AC: 137 AN: 53892

GnomAD4 genome AF: 0.00183 AC: 263 AN: 143482 Hom.: 2 Cov.: 24 AF XY: 0.00194 AC XY: 136 AN XY: 70066

African (AFR) AF: 0.00148 AC: 58 AN: 39244

American (AMR) AF: 0.00136 AC: 20 AN: 14660

Ashkenazi Jewish (ASJ) AF: 0.00625 AC: 20 AN: 3200

East Asian (EAS) AF: 0.00386 AC: 19 AN: 4916

South Asian (SAS) AF: 0.00583 AC: 27 AN: 4628

European-Finnish (FIN) AF: 0.00100 AC: 10 AN: 9992

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.00163 AC: 104 AN: 63758

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

Alfa AF: 0.000616 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		0.29
Mutation Taster		=54/46	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;