6-170561958-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr6-170561958-ACAGCAGCAGCAGCAG-A
• rs752404282
• NM_003194.5:c.267_281delGCAGCAGCAGCAGCA

Variant summary

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

The ENST00000392092.7(TBP):​c.267_281delGCAGCAGCAGCAGCA​(p.Gln90_Gln94del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000216 in 143,472 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP ENST00000392092.7 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• 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: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000392092.7
• BS2: High AC in GnomAd4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000392092.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.267_281delGCAGCAGCAGCAGCA	p.Gln90_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1
	TBP	NM_001172085.2		c.207_221delGCAGCAGCAGCAGCA	p.Gln70_Gln74del	disruptive_inframe_deletion	Exon 2 of 7	NP_001165556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.267_281delGCAGCAGCAGCAGCA	p.Gln90_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2
	TBP	ENST00000230354.10	TSL:1	c.267_281delGCAGCAGCAGCAGCA	p.Gln90_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5
	TBP	ENST00000421512.5	TSL:1	c.267_281delGCAGCAGCAGCAGCA	p.Gln90_Gln94del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1

Frequencies

GnomAD3 genomes AF: 0.000202 AC: 29 AN: 143368 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.00101

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000999 AC: 126 AN: 1261676 Hom.: 0 AF XY: 0.0000840 AC XY: 53 AN XY: 630686

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000869 AC: 25 AN: 28774

American (AMR) AF: 0.0000477 AC: 2 AN: 41890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23726

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38406

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81726

European-Finnish (FIN) AF: 0.000108 AC: 5 AN: 46476

Middle Eastern (MID) AF: 0.000202 AC: 1 AN: 4954

European-Non Finnish (NFE) AF: 0.0000892 AC: 84 AN: 941830

Other (OTH) AF: 0.000130 AC: 7 AN: 53894

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000216 AC: 31 AN: 143472 Hom.: 0 Cov.: 21 AF XY: 0.000257 AC XY: 18 AN XY: 70058

African (AFR) AF: 0.000535 AC: 21 AN: 39240

American (AMR) AF: 0.00 AC: 0 AN: 14660

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

East Asian (EAS) AF: 0.000203 AC: 1 AN: 4916

South Asian (SAS) AF: 0.00 AC: 0 AN: 4628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9992

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

European-Non Finnish (NFE) AF: 0.0000941 AC: 6 AN: 63756

Other (OTH) AF: 0.00150 AC: 3 AN: 1996

Alfa AF: 0.00 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=169/31	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;