chr6-170561958-A-ACAGCAG

Variant names:

• chr6-170561958-A-ACAGCAG
• rs752404282
• NM_003194.5:c.276_281dupGCAGCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_003194.5(TBP):​c.276_281dupGCAGCA​(p.Gln93_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 0.00471 in 1,404,802 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 24)
  • Exomes 𝑓: 0.0048 (19 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Likely 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: Benign. The variant received -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561958-A-ACAGCAG is Benign according to our data. Variant chr6-170561958-A-ACAGCAG is described in ClinVar as Likely_benign. ClinVar VariationId is 445790.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 601 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.276_281dupGCAGCA	p.Gln93_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.216_221dupGCAGCA	p.Gln73_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.276_281dupGCAGCA	p.Gln93_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.276_281dupGCAGCA	p.Gln93_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.276_281dupGCAGCA	p.Gln93_Gln94dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 600 AN: 143368 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00355

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00852

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.000901

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00436

Gnomad OTH AF: 0.00253

GnomAD2 exomes AF: 0.00435 AC: 651 AN: 149640 AF XY: 0.00440

Gnomad AFR exome AF: 0.00394

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.000594

Gnomad NFE exome AF: 0.00325

Gnomad OTH exome AF: 0.00207

GnomAD4 exome AF: 0.00476 AC: 6009 AN: 1261328 Hom.: 19 Cov.: 0 AF XY: 0.00496 AC XY: 3129 AN XY: 630480

African (AFR) AF: 0.00372 AC: 107 AN: 28774

American (AMR) AF: 0.00341 AC: 143 AN: 41886

Ashkenazi Jewish (ASJ) AF: 0.000506 AC: 12 AN: 23728

East Asian (EAS) AF: 0.00604 AC: 232 AN: 38388

South Asian (SAS) AF: 0.0104 AC: 847 AN: 81662

European-Finnish (FIN) AF: 0.00105 AC: 49 AN: 46474

Middle Eastern (MID) AF: 0.00384 AC: 19 AN: 4954

European-Non Finnish (NFE) AF: 0.00458 AC: 4309 AN: 941574

Other (OTH) AF: 0.00540 AC: 291 AN: 53888

GnomAD4 genome AF: 0.00419 AC: 601 AN: 143474 Hom.: 2 Cov.: 24 AF XY: 0.00387 AC XY: 271 AN XY: 70062

African (AFR) AF: 0.00392 AC: 154 AN: 39242

American (AMR) AF: 0.00355 AC: 52 AN: 14660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3200

East Asian (EAS) AF: 0.00854 AC: 42 AN: 4916

South Asian (SAS) AF: 0.0130 AC: 60 AN: 4626

European-Finnish (FIN) AF: 0.000901 AC: 9 AN: 9992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.00436 AC: 278 AN: 63756

Other (OTH) AF: 0.00300 AC: 6 AN: 1998

Alfa AF: 0.00148 Hom.: 4

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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;