chr6-170561966-AGCAGCAGCAGCAGCAGCAGCAGCAG-A

Position:

• chr6-170561966-AGCAGCAGCAGCAGCAGCAGCAGCAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_003194.5(TBP):​c.231_255del​(p.Gln77HisfsTer59) variant causes a frameshift change. The variant allele was found at a frequency of 0.000321 in 1,292,508 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q77Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.231_255del	p.Gln77HisfsTer59	frameshift_variant	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.171_195del	p.Gln57HisfsTer59	frameshift_variant	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.231_255del	p.Gln77HisfsTer59	frameshift_variant	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.000650 AC: 92 AN: 141542 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000483

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000222

Gnomad SAS AF: 0.000466

Gnomad FIN AF: 0.0000984

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000431

Gnomad OTH AF: 0.00103

GnomAD4 exome AF: 0.000282 AC: 324 AN: 1150864 Hom.: 2 AF XY: 0.000294 AC XY: 169 AN XY: 575650

Gnomad4 AFR exome AF: 0.000768

Gnomad4 AMR exome AF: 0.000138

Gnomad4 ASJ exome AF: 0.0000947

Gnomad4 EAS exome AF: 0.000402

Gnomad4 SAS exome AF: 0.000269

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000642 AC: 91 AN: 141644 Hom.: 0 Cov.: 25 AF XY: 0.000552 AC XY: 38 AN XY: 68818

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.000483

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000222

Gnomad4 SAS AF: 0.000466

Gnomad4 FIN AF: 0.0000984

Gnomad4 NFE AF: 0.000431

Gnomad4 OTH AF: 0.00102

Alfa AF: 0.00337 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Arun Kumar Laboratory, Indian Institute of Science

Jun 15, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1779152934; hg19: chr6-170871054;