rs1491487452

Positions:

• chr6-170561963-AGC-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_003194.5(TBP):​c.228_229del​(p.Gln77AlafsTer100) variant causes a frameshift change. The variant allele was found at a frequency of 0.296 in 661,170 control chromosomes in the GnomAD database, including 36,712 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q76Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.37 (11016 hom., cov: 21)
  • Exomes 𝑓: 0.28 (25696 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.78

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 Benign. Variant got -8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 6-170561963-AGC-A is Benign according to our data. Variant chr6-170561963-AGC-A is described in ClinVar as [Benign]. Clinvar id is 403524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-170561963-AGC-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.228_229del	p.Gln77AlafsTer100	frameshift_variant	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.168_169del	p.Gln57AlafsTer100	frameshift_variant	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.228_229del	p.Gln77AlafsTer100	frameshift_variant	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.366 AC: 48502 AN: 132638 Hom.: 11006 Cov.: 21

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.328

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.353

GnomAD3 exomes AF: 0.0697 AC: 12096 AN: 173514 Hom.: 230 AF XY: 0.0625 AC XY: 6026 AN XY: 96468

Gnomad AFR exome AF: 0.288

Gnomad AMR exome AF: 0.0665

Gnomad ASJ exome AF: 0.0754

Gnomad EAS exome AF: 0.245

Gnomad SAS exome AF: 0.0516

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0431

Gnomad OTH exome AF: 0.0740

GnomAD4 exome AF: 0.279 AC: 147219 AN: 528434 Hom.: 25696 AF XY: 0.289 AC XY: 78543 AN XY: 271860

Gnomad4 AFR exome AF: 0.673

Gnomad4 AMR exome AF: 0.392

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.690

Gnomad4 SAS exome AF: 0.388

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.366 AC: 48553 AN: 132736 Hom.: 11016 Cov.: 21 AF XY: 0.356 AC XY: 22899 AN XY: 64402

Gnomad4 AFR AF: 0.661

Gnomad4 AMR AF: 0.273

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.122

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1491487452; hg19: chr6-170871051; COSMIC: COSV57830655;