6-170561925-ACAGCAGCAGCAGCAG-ACAGCAGCAGCAG

Variant names:

• chr6-170561925-ACAG-A
• rs113202486
• NM_003194.5:c.213_215delGCA

Variant summary

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

The NM_003194.5(TBP):​c.213_215delGCA​(p.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 0.00123 in 981,272 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (2 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 187 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.213_215delGCA	p.Gln72del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.153_155delGCA	p.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.213_215delGCA	p.Gln72del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.213_215delGCA	p.Gln72del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.213_215delGCA	p.Gln72del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 185 AN: 127366 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000423

Gnomad ASJ AF: 0.000315

Gnomad EAS AF: 0.00809

Gnomad SAS AF: 0.00161

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000408

Gnomad OTH AF: 0.00247

GnomAD4 exome AF: 0.00119 AC: 1019 AN: 853810 Hom.: 2 AF XY: 0.00110 AC XY: 488 AN XY: 442598

African (AFR) AF: 0.00522 AC: 99 AN: 18962

American (AMR) AF: 0.000691 AC: 26 AN: 37644

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 25 AN: 21622

East Asian (EAS) AF: 0.00745 AC: 255 AN: 34234

South Asian (SAS) AF: 0.000864 AC: 59 AN: 68288

European-Finnish (FIN) AF: 0.000756 AC: 32 AN: 42304

Middle Eastern (MID) AF: 0.00114 AC: 4 AN: 3518

European-Non Finnish (NFE) AF: 0.000790 AC: 464 AN: 587480

Other (OTH) AF: 0.00138 AC: 55 AN: 39758

GnomAD4 genome AF: 0.00147 AC: 187 AN: 127462 Hom.: 0 Cov.: 0 AF XY: 0.00147 AC XY: 89 AN XY: 60416

African (AFR) AF: 0.00334 AC: 111 AN: 33254

American (AMR) AF: 0.000422 AC: 5 AN: 11846

Ashkenazi Jewish (ASJ) AF: 0.000315 AC: 1 AN: 3176

East Asian (EAS) AF: 0.00812 AC: 33 AN: 4066

South Asian (SAS) AF: 0.00161 AC: 5 AN: 3112

European-Finnish (FIN) AF: 0.000376 AC: 3 AN: 7980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.000408 AC: 25 AN: 61322

Other (OTH) AF: 0.00244 AC: 4 AN: 1636

Alfa AF: 0.000180 Hom.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs113202486; hg19: chr6-170871013; COSMIC: COSV105853264;