6-170561966-AGCAGCAGCAG-A

Position:

• chr6-170561966-AGCAGCAGCAG-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BA1

The NM_003194.5(TBP):​c.231_240del​(p.Gln77HisfsTer64) variant causes a frameshift change. The variant allele was found at a frequency of 0.00578 in 1,288,298 control chromosomes in the GnomAD database, including 261 homozygotes. Variant has been reported in ClinVar as 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 0.032 (228 hom., cov: 25)
  • Exomes 𝑓: 0.0025 (33 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Benign no assertion criteria provided B:2
• 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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 6-170561966-AGCAGCAGCAG-A is Benign according to our data. Variant chr6-170561966-AGCAGCAGCAG-A is described in ClinVar as [Benign]. Clinvar id is 1174728.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-170561966-AGCAGCAGCAG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.231_240del	p.Gln77HisfsTer64	frameshift_variant	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.171_180del	p.Gln57HisfsTer64	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_240del	p.Gln77HisfsTer64	frameshift_variant	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4555 AN: 141354 Hom.: 227 Cov.: 25

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0151

Gnomad SAS AF: 0.00326

Gnomad FIN AF: 0.00246

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.00392 AC: 723 AN: 184244 Hom.: 1 AF XY: 0.00288 AC XY: 296 AN XY: 102778

Gnomad AFR exome AF: 0.0645

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00938

Gnomad SAS exome AF: 0.000119

Gnomad FIN exome AF: 0.000298

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00251 AC: 2884 AN: 1146844 Hom.: 33 AF XY: 0.00235 AC XY: 1347 AN XY: 573954

Gnomad4 AFR exome AF: 0.0690

Gnomad4 AMR exome AF: 0.00457

Gnomad4 ASJ exome AF: 0.00895

Gnomad4 EAS exome AF: 0.00656

Gnomad4 SAS exome AF: 0.000902

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.000465

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.0323 AC: 4567 AN: 141454 Hom.: 228 Cov.: 25 AF XY: 0.0316 AC XY: 2169 AN XY: 68740

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.0149

Gnomad4 SAS AF: 0.00303

Gnomad4 FIN AF: 0.00246

Gnomad4 NFE AF: 0.00155

Gnomad4 OTH AF: 0.0189

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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: rs773085804; hg19: chr6-170871054;