NM_003194.5:c.213_215dupGCA

Variant names:

• chr6-170561925-A-ACAG
• rs113202486
• NM_003194.5:c.213_215dupGCA

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_003194.5(TBP):​c.213_215dupGCA​(p.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 0.0478 in 979,026 control chromosomes in the GnomAD database, including 3,426 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q72Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.061 (413 hom., cov: 0)
  • Exomes 𝑓: 0.046 (3013 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561925-A-ACAG is Benign according to our data. Variant chr6-170561925-A-ACAG is described in ClinVar as [Benign]. Clinvar id is 1221615.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.213_215dupGCA	p.Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.153_155dupGCA	p.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.213_215dupGCA	p.Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 7697 AN: 127140 Hom.: 412 Cov.: 0

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0350

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.0760

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.100

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0593

GnomAD4 exome AF: 0.0459 AC: 39115 AN: 851790 Hom.: 3013 Cov.: 79 AF XY: 0.0464 AC XY: 20454 AN XY: 441252

Gnomad4 AFR exome AF: 0.0458

Gnomad4 AMR exome AF: 0.0444

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.0398

Gnomad4 SAS exome AF: 0.0599

Gnomad4 FIN exome AF: 0.0893

Gnomad4 NFE exome AF: 0.0421

Gnomad4 OTH exome AF: 0.0478

GnomAD4 genome AF: 0.0606 AC: 7713 AN: 127236 Hom.: 413 Cov.: 0 AF XY: 0.0633 AC XY: 3817 AN XY: 60316

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.0524

Gnomad4 ASJ AF: 0.0350

Gnomad4 EAS AF: 0.0234

Gnomad4 SAS AF: 0.0754

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0662

Gnomad4 OTH AF: 0.0587

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

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

LitVar

Other links and lift over

dbSNP: rs113202486; hg19: chr6-170871013;