6-170561925-ACAGCAGCAGCAGCAG-ACAGCAGCAG

Variant names:

• chr6-170561925-ACAGCAG-A
• rs113202486
• NM_003194.5:c.210_215delGCAGCA

Variant summary

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

The NM_003194.5(TBP):​c.210_215delGCAGCA​(p.Gln71_Gln72del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 981,386 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00069 (1 hom.)
• 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 -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BS2: High AC in GnomAd4 at 56 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.210_215delGCAGCA	p.Gln71_Gln72del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.150_155delGCAGCA	p.Gln51_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.210_215delGCAGCA	p.Gln71_Gln72del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.210_215delGCAGCA	p.Gln71_Gln72del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.210_215delGCAGCA	p.Gln71_Gln72del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 56 AN: 127366 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000338

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00319

Gnomad SAS AF: 0.00385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000359

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000692 AC: 591 AN: 853926 Hom.: 1 AF XY: 0.000752 AC XY: 333 AN XY: 442654

African (AFR) AF: 0.0000527 AC: 1 AN: 18962

American (AMR) AF: 0.000159 AC: 6 AN: 37648

Ashkenazi Jewish (ASJ) AF: 0.0000462 AC: 1 AN: 21622

East Asian (EAS) AF: 0.00269 AC: 92 AN: 34236

South Asian (SAS) AF: 0.00250 AC: 171 AN: 68288

European-Finnish (FIN) AF: 0.0000473 AC: 2 AN: 42316

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

European-Non Finnish (NFE) AF: 0.000488 AC: 287 AN: 587572

Other (OTH) AF: 0.000780 AC: 31 AN: 39764

GnomAD4 genome AF: 0.000439 AC: 56 AN: 127460 Hom.: 0 Cov.: 0 AF XY: 0.000480 AC XY: 29 AN XY: 60416

African (AFR) AF: 0.000150 AC: 5 AN: 33252

American (AMR) AF: 0.000338 AC: 4 AN: 11846

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

East Asian (EAS) AF: 0.00320 AC: 13 AN: 4064

South Asian (SAS) AF: 0.00386 AC: 12 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: 0.000359 AC: 22 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		=135/65	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;