NM_003194.5:c.210_215dupGCAGCA

Variant names:

• chr6-170561925-A-ACAGCAG
• rs113202486
• NM_003194.5:c.210_215dupGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS2_Supporting

The NM_003194.5(TBP):​c.210_215dupGCAGCA​(p.Gln71_Gln72dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 981,382 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q72Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40
• 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 -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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_215dupGCAGCA	p.Gln71_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.150_155dupGCAGCA	p.Gln51_Gln52dup	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.210_215dupGCAGCA	p.Gln71_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.210_215dupGCAGCA	p.Gln71_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.210_215dupGCAGCA	p.Gln71_Gln72dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.0000393 AC: 5 AN: 127368 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.0000326

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000398 AC: 34 AN: 853918 Hom.: 0 Cov.: 79 AF XY: 0.0000294 AC XY: 13 AN XY: 442648

African (AFR) AF: 0.000264 AC: 5 AN: 18962

American (AMR) AF: 0.00 AC: 0 AN: 37648

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

East Asian (EAS) AF: 0.0000876 AC: 3 AN: 34236

South Asian (SAS) AF: 0.0000293 AC: 2 AN: 68288

European-Finnish (FIN) AF: 0.0000236 AC: 1 AN: 42316

Middle Eastern (MID) AF: 0.000284 AC: 1 AN: 3518

European-Non Finnish (NFE) AF: 0.0000323 AC: 19 AN: 587566

Other (OTH) AF: 0.0000503 AC: 2 AN: 39762

GnomAD4 genome AF: 0.0000392 AC: 5 AN: 127464 Hom.: 0 Cov.: 0 AF XY: 0.0000662 AC XY: 4 AN XY: 60418

African (AFR) AF: 0.0000601 AC: 2 AN: 33254

American (AMR) AF: 0.00 AC: 0 AN: 11846

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4066

South Asian (SAS) AF: 0.00 AC: 0 AN: 3112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7980

Middle Eastern (MID) AF: 0.00397 AC: 1 AN: 252

European-Non Finnish (NFE) AF: 0.0000326 AC: 2 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		2.4
Mutation Taster		=60/40	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;