rs1491487452

Variant names:

• chr6-170561963-AGC-A
• rs1491487452
• NM_003194.5:c.228_229delGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003194.5(TBP):​c.228_229delGC​(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. 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. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q76Q) has been classified as Likely 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:3
• Conservation: PhyloP100: 3.78
• Publications: 6 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-170561963-AGC-A is Benign according to our data. Variant chr6-170561963-AGC-A is described in ClinVar as Benign. ClinVar VariationId is 403524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.228_229delGC	p.Gln77AlafsTer100	frameshift_variant	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.168_169delGC	p.Gln57AlafsTer100	frameshift_variant	Exon 2 of 7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.228_229delGC	p.Gln77AlafsTer100	frameshift_variant	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

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

GnomAD2 exomes AF: 0.0697 AC: 12096 AN: 173514 AF XY: 0.0625

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 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

African (AFR) AF: 0.673 AC: 8925 AN: 13256

American (AMR) AF: 0.392 AC: 6923 AN: 17664

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 6220 AN: 12630

East Asian (EAS) AF: 0.690 AC: 20486 AN: 29676

South Asian (SAS) AF: 0.388 AC: 15353 AN: 39618

European-Finnish (FIN) AF: 0.210 AC: 4498 AN: 21376

Middle Eastern (MID) AF: 0.382 AC: 965 AN: 2524

European-Non Finnish (NFE) AF: 0.205 AC: 75088 AN: 366396

Other (OTH) AF: 0.346 AC: 8761 AN: 25294

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

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

African (AFR) AF: 0.661 AC: 23080 AN: 34910

American (AMR) AF: 0.273 AC: 3675 AN: 13474

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1353 AN: 3142

East Asian (EAS) AF: 0.571 AC: 2441 AN: 4272

South Asian (SAS) AF: 0.285 AC: 1140 AN: 4000

European-Finnish (FIN) AF: 0.122 AC: 1166 AN: 9526

Middle Eastern (MID) AF: 0.330 AC: 89 AN: 270

European-Non Finnish (NFE) AF: 0.244 AC: 14759 AN: 60490

Other (OTH) AF: 0.355 AC: 649 AN: 1826

⚠️ 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.

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Spinocerebellar ataxia type 17;C3160718:Parkinson disease, late-onset Benign:1

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=198/2	polymorphism (auto)

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

Other links and lift over

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