NM_003194.5:c.215_216insGCAACAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant names:

• chr6-170561925-A-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAACAACAG
• NM_003194.5:c.215_216insGCAACAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP3

The NM_003194.5(TBP):​c.215_216insGCAACAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCA​(p.Gln60_Gln72dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q72Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.40

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-170561925-A-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAACAACAG is Pathogenic according to our data. Variant chr6-170561925-A-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAACAACAACAG is described in ClinVar as [Pathogenic]. Clinvar id is 3572894.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 rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.215_216insGCAACAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln60_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.155_156insGCAACAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln40_Gln52dup	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.215_216insGCAACAACAACAGCAGCAGCAGCAGCAGCAGCAGCAGCA	p.Gln60_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 17 Pathogenic:1

Dec 18, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-170871013;