NM_003194.5:c.207_215dupGCAGCAGCA

Variant names:

• chr6-170561925-A-ACAGCAGCAG
• rs113202486
• NM_003194.5:c.207_215dupGCAGCAGCA

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_003194.5(TBP):​c.207_215dupGCAGCAGCA​(p.Gln70_Gln72dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000704 in 981,328 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q72Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00069 (17 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B: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 Benign. Variant got -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561925-A-ACAGCAGCAG is Benign according to our data. Variant chr6-170561925-A-ACAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 3390327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.207_215dupGCAGCAGCA	p.Gln70_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.147_155dupGCAGCAGCA	p.Gln50_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.207_215dupGCAGCAGCA	p.Gln70_Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes AF: 0.000817 AC: 104 AN: 127362 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000181

Gnomad AMI AF: 0.00122

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000736

Gnomad SAS AF: 0.000321

Gnomad FIN AF: 0.000125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000978

Gnomad OTH AF: 0.000617

GnomAD4 exome AF: 0.000687 AC: 587 AN: 853870 Hom.: 17 Cov.: 79 AF XY: 0.000718 AC XY: 318 AN XY: 442618

Gnomad4 AFR exome AF: 0.000369

Gnomad4 AMR exome AF: 0.000611

Gnomad4 ASJ exome AF: 0.000277

Gnomad4 EAS exome AF: 0.000438

Gnomad4 SAS exome AF: 0.000103

Gnomad4 FIN exome AF: 0.000922

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000816 AC: 104 AN: 127458 Hom.: 0 Cov.: 0 AF XY: 0.000944 AC XY: 57 AN XY: 60412

Gnomad4 AFR AF: 0.000180

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000738

Gnomad4 SAS AF: 0.000322

Gnomad4 FIN AF: 0.000125

Gnomad4 NFE AF: 0.000978

Gnomad4 OTH AF: 0.000611

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBP: BS2 -

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: rs113202486; hg19: chr6-170871013;