chr6-170561958-ACAGCAG-A

Variant names:

• chr6-170561958-ACAGCAG-A
• rs752404282
• NM_003194.5:c.276_281delGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_003194.5(TBP):​c.276_281delGCAGCA​(p.Gln93_Gln94del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,403,562 control chromosomes in the GnomAD database, including 259 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (46 hom., cov: 21)
  • Exomes 𝑓: 0.010 (213 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5

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_281delGCAGCA	p.Gln93_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.216_221delGCAGCA	p.Gln73_Gln74del	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.276_281delGCAGCA	p.Gln93_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.276_281delGCAGCA	p.Gln93_Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.276_281delGCAGCA	p.Gln93_Gln94del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2413 AN: 142992 Hom.: 46 Cov.: 21

Gnomad AFR AF: 0.00829

Gnomad AMI AF: 0.0160

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000609

Gnomad SAS AF: 0.00801

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0139

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0233

GnomAD2 exomes AF: 0.00957 AC: 1432 AN: 149640 AF XY: 0.00939

Gnomad AFR exome AF: 0.00686

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00663

Gnomad EAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0102 AC: 12909 AN: 1260464 Hom.: 213 AF XY: 0.0101 AC XY: 6388 AN XY: 630040

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

African (AFR) AF: 0.00476 AC: 137 AN: 28758

American (AMR) AF: 0.0109 AC: 455 AN: 41842

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 256 AN: 23704

East Asian (EAS) AF: 0.000859 AC: 33 AN: 38396

South Asian (SAS) AF: 0.00676 AC: 552 AN: 81670

European-Finnish (FIN) AF: 0.0170 AC: 788 AN: 46354

Middle Eastern (MID) AF: 0.00993 AC: 49 AN: 4934

European-Non Finnish (NFE) AF: 0.0106 AC: 9987 AN: 940966

Other (OTH) AF: 0.0121 AC: 652 AN: 53840

⚠️ 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: 0.0169 AC: 2413 AN: 143098 Hom.: 46 Cov.: 21 AF XY: 0.0167 AC XY: 1168 AN XY: 69886

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

African (AFR) AF: 0.00835 AC: 327 AN: 39178

American (AMR) AF: 0.0189 AC: 276 AN: 14614

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 77 AN: 3184

East Asian (EAS) AF: 0.000610 AC: 3 AN: 4916

South Asian (SAS) AF: 0.00780 AC: 36 AN: 4618

European-Finnish (FIN) AF: 0.0217 AC: 216 AN: 9956

Middle Eastern (MID) AF: 0.0149 AC: 4 AN: 268

European-Non Finnish (NFE) AF: 0.0223 AC: 1415 AN: 63558

Other (OTH) AF: 0.0231 AC: 46 AN: 1992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0107 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=192/8	polymorphism (auto)

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;