chr6-170561966-AGCAGCAGCAGCAGCAG-A

Position:

• chr6-170561966-AGCAGCAGCAGCAGCAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_003194.5(TBP):​c.231_246del​(p.Gln77HisfsTer62) variant causes a frameshift change. The variant allele was found at a frequency of 0.00151 in 1,290,046 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in Lovd as Likely benign (no stars). 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 0.0024 (3 hom., cov: 25)
  • Exomes 𝑓: 0.0014 (11 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 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 6-170561966-AGCAGCAGCAGCAGCAG-A is Benign according to our data. Variant chr6-170561966-AGCAGCAGCAGCAGCAG-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.231_246del	p.Gln77HisfsTer62	frameshift_variant	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.171_186del	p.Gln57HisfsTer62	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_246del	p.Gln77HisfsTer62	frameshift_variant	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 342 AN: 141528 Hom.: 3 Cov.: 25

Gnomad AFR AF: 0.00156

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.0212

Gnomad EAS AF: 0.00177

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00362

GnomAD4 exome AF: 0.00139 AC: 1601 AN: 1148416 Hom.: 11 AF XY: 0.00158 AC XY: 910 AN XY: 574418

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.000891

Gnomad4 SAS exome AF: 0.00447

Gnomad4 FIN exome AF: 0.0000507

Gnomad4 NFE exome AF: 0.000752

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00241 AC: 341 AN: 141630 Hom.: 3 Cov.: 25 AF XY: 0.00256 AC XY: 176 AN XY: 68810

Gnomad4 AFR AF: 0.00155

Gnomad4 AMR AF: 0.00400

Gnomad4 ASJ AF: 0.0212

Gnomad4 EAS AF: 0.00178

Gnomad4 SAS AF: 0.00536

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00358

Alfa AF: 0.00253 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: rs1779152778; hg19: chr6-170871054;