6-170561958-A-ACAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_Moderate BP3

The NM_003194.5(TBP):c.264_281dup(p.Gln90_Gln95dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,405,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: TBP NM_003194.5 inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 6-170561958-A-ACAGCAGCAGCAGCAGCAG is Pathogenic according to our data. Variant chr6-170561958-A-ACAGCAGCAGCAGCAGCAG is described in ClinVar as [Pathogenic]. Clinvar id is 2576597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP3: Nonframeshift variant in repetitive region in NM_003194.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBP	NM_003194.5	c.264_281dup	p.Gln90_Gln95dup	inframe_insertion	3/8	ENST00000392092.7
TBP	NM_001172085.2	c.204_221dup	p.Gln70_Gln75dup	inframe_insertion	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBP	ENST00000392092.7	c.264_281dup	p.Gln90_Gln95dup	inframe_insertion	3/8	1	NM_003194.5	P2

Frequencies

GnomAD3 genomes AF: 0.000181 AC: 26 AN: 143372 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.000313

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.000432

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000761 AC: 96 AN: 1261698 Hom.: 0 Cov.: 0 AF XY: 0.0000904 AC XY: 57 AN XY: 630694

Gnomad4 AFR exome AF: 0.0000348

Gnomad4 AMR exome AF: 0.000215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000208

Gnomad4 SAS exome AF: 0.000196

Gnomad4 FIN exome AF: 0.0000215

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.000204

GnomAD4 genome AF: 0.000181 AC: 26 AN: 143478 Hom.: 0 Cov.: 24 AF XY: 0.000143 AC XY: 10 AN XY: 70064

Gnomad4 AFR AF: 0.000204

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.000313

Gnomad4 EAS AF: 0.000203

Gnomad4 SAS AF: 0.000432

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 17 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

May 24, 2023

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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;