6-170561958-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr6-170561958-A-ACAG
• rs752404282
• NM_003194.5:c.279_281dupGCA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_003194.5(TBP):​c.279_281dupGCA​(p.Gln94dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 143,480 control chromosomes in the GnomAD database, including 39 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (39 hom., cov: 24)
  • Exomes 𝑓: 0.022 (2508 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290

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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2378/143480) while in subpopulation NFE AF= 0.02 (1278/63758). AF 95% confidence interval is 0.0191. There are 39 homozygotes in gnomad4. There are 1097 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.279_281dupGCA	p.Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.219_221dupGCA	p.Gln74dup	disruptive_inframe_insertion	Exon 2 of 7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.279_281dupGCA	p.Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2372 AN: 143374 Hom.: 39 Cov.: 24

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00368

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.0117

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0345

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.0180 AC: 2687 AN: 149640 Hom.: 0 AF XY: 0.0176 AC XY: 1440 AN XY: 81604

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0197

Gnomad SAS exome AF: 0.0250

Gnomad FIN exome AF: 0.00502

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0284

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0220 AC: 27715 AN: 1261082 Hom.: 2508 Cov.: 0 AF XY: 0.0215 AC XY: 13546 AN XY: 630374

Gnomad4 AFR exome AF: 0.0164

Gnomad4 AMR exome AF: 0.0179

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0137

Gnomad4 SAS exome AF: 0.0187

Gnomad4 FIN exome AF: 0.00947

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0166 AC: 2378 AN: 143480 Hom.: 39 Cov.: 24 AF XY: 0.0157 AC XY: 1097 AN XY: 70058

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0103

Gnomad4 EAS AF: 0.0120

Gnomad4 SAS AF: 0.0117

Gnomad4 FIN AF: 0.0110

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0160

ClinVar

Not reported in ClinVar

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: rs752404282; hg19: chr6-170871046;