chr6-170561966-AGCAGCAGCAG-A

Variant names:

• chr6-170561966-AGCAGCAGCAG-A
• rs773085804
• NM_003194.5:c.231_240delGCAGCAGCAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_003194.5(TBP):​c.231_240delGCAGCAGCAG​(p.Gln77HisfsTer64) variant causes a frameshift change. The variant allele was found at a frequency of 0.00578 in 1,288,298 control chromosomes in the GnomAD database, including 261 homozygotes. Variant has been reported in ClinVar as Benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.032 (228 hom., cov: 25)
  • Exomes 𝑓: 0.0025 (33 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Benign no assertion criteria provided B:2
• Conservation: PhyloP100: 5.03
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 6-170561966-AGCAGCAGCAG-A is Benign according to our data. Variant chr6-170561966-AGCAGCAGCAG-A is described in ClinVar as Benign. ClinVar VariationId is 1174728.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

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.231_240delGCAGCAGCAG	p.Gln77HisfsTer64	frameshift	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.171_180delGCAGCAGCAG	p.Gln57HisfsTer64	frameshift	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.231_240delGCAGCAGCAG	p.Gln77HisfsTer64	frameshift	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.231_240delGCAGCAGCAG	p.Gln77HisfsTer64	frameshift	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.231_240delGCAGCAGCAG	p.Gln77HisfsTer64	frameshift	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4555 AN: 141354 Hom.: 227 Cov.: 25

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0151

Gnomad SAS AF: 0.00326

Gnomad FIN AF: 0.00246

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.00392 AC: 723 AN: 184244 AF XY: 0.00288

Gnomad AFR exome AF: 0.0645

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00938

Gnomad FIN exome AF: 0.000298

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00251 AC: 2884 AN: 1146844 Hom.: 33 AF XY: 0.00235 AC XY: 1347 AN XY: 573954

African (AFR) AF: 0.0690 AC: 1435 AN: 20798

American (AMR) AF: 0.00457 AC: 165 AN: 36144

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 188 AN: 21000

East Asian (EAS) AF: 0.00656 AC: 228 AN: 34748

South Asian (SAS) AF: 0.000902 AC: 67 AN: 74298

European-Finnish (FIN) AF: 0.00183 AC: 72 AN: 39388

Middle Eastern (MID) AF: 0.00579 AC: 28 AN: 4838

European-Non Finnish (NFE) AF: 0.000465 AC: 403 AN: 866798

Other (OTH) AF: 0.00610 AC: 298 AN: 48832

GnomAD4 genome AF: 0.0323 AC: 4567 AN: 141454 Hom.: 228 Cov.: 25 AF XY: 0.0316 AC XY: 2169 AN XY: 68740

African (AFR) AF: 0.112 AC: 4103 AN: 36590

American (AMR) AF: 0.0124 AC: 180 AN: 14492

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 36 AN: 3352

East Asian (EAS) AF: 0.0149 AC: 67 AN: 4496

South Asian (SAS) AF: 0.00303 AC: 13 AN: 4286

European-Finnish (FIN) AF: 0.00246 AC: 25 AN: 10154

Middle Eastern (MID) AF: 0.0177 AC: 5 AN: 282

European-Non Finnish (NFE) AF: 0.00155 AC: 101 AN: 64968

Other (OTH) AF: 0.0189 AC: 37 AN: 1954

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=174/26	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs773085804; hg19: chr6-170871054;