chr6-170561958-ACAGCAG-A

Position:

• chr6-170561958-ACAGCAG-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The ENST00000392092.7(TBP):​c.276_281del​(p.Gln94_Gln95del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,403,562 control chromosomes in the GnomAD database, including 259 homozygotes. Variant has been reported in Lovd as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. Q75Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (46 hom., cov: 21)
  • Exomes 𝑓: 0.010 (213 hom.)
• Consequence: TBP ENST00000392092.7 inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36

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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000392092.7
• BP6: Variant 6-170561958-ACAGCAG-A is Benign according to our data. Variant chr6-170561958-ACAGCAG-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0169 (2413/143098) while in subpopulation NFE AF= 0.0223 (1415/63558). AF 95% confidence interval is 0.0213. There are 46 homozygotes in gnomad4. There are 1168 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.276_281del	p.Gln94_Gln95del	inframe_deletion	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.216_221del	p.Gln74_Gln75del	inframe_deletion	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.276_281del	p.Gln94_Gln95del	inframe_deletion	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2413 AN: 142992 Hom.: 46 Cov.: 21

Gnomad AFR AF: 0.00829

Gnomad AMI AF: 0.0160

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.000609

Gnomad SAS AF: 0.00801

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.0139

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0233

GnomAD3 exomes AF: 0.00957 AC: 1432 AN: 149640 Hom.: 70 AF XY: 0.00939 AC XY: 766 AN XY: 81604

Gnomad AFR exome AF: 0.00686

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00663

Gnomad EAS exome AF: 0.00229

Gnomad SAS exome AF: 0.00603

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.0151

GnomAD4 exome AF: 0.0102 AC: 12909 AN: 1260464 Hom.: 213 AF XY: 0.0101 AC XY: 6388 AN XY: 630040

Gnomad4 AFR exome AF: 0.00476

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.000859

Gnomad4 SAS exome AF: 0.00676

Gnomad4 FIN exome AF: 0.0170

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0169 AC: 2413 AN: 143098 Hom.: 46 Cov.: 21 AF XY: 0.0167 AC XY: 1168 AN XY: 69886

Gnomad4 AFR AF: 0.00835

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.000610

Gnomad4 SAS AF: 0.00780

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0223

Gnomad4 OTH AF: 0.0231

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;