chr6-170561949-GCAA-G

Position:

• chr6-170561949-GCAA-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_003194.5(TBP):​c.216_218delACA​(p.Gln73del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 943,134 control chromosomes in the GnomAD database, including 104,387 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 0.77 (36212 hom., cov: 0)
  • Exomes 𝑓: 0.36 (68175 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.76

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 -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561949-GCAA-G is Benign according to our data. Variant chr6-170561949-GCAA-G is described in ClinVar as [Benign]. Clinvar id is 522261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-170561949-GCAA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.216_218delACA	p.Gln73del	disruptive_inframe_deletion	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.156_158delACA	p.Gln53del	disruptive_inframe_deletion	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.216_218delACA	p.Gln73del	disruptive_inframe_deletion	3/8	1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes AF: 0.770 AC: 92821 AN: 120586 Hom.: 36201 Cov.: 0

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.903

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.800

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.766

GnomAD3 exomes AF: 0.278 AC: 35686 AN: 128308 Hom.: 2663 AF XY: 0.266 AC XY: 18183 AN XY: 68434

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.426

Gnomad SAS exome AF: 0.252

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.356 AC: 292805 AN: 822476 Hom.: 68175 AF XY: 0.372 AC XY: 156332 AN XY: 420124

Gnomad4 AFR exome AF: 0.557

Gnomad4 AMR exome AF: 0.475

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.714

Gnomad4 SAS exome AF: 0.531

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.770 AC: 92871 AN: 120658 Hom.: 36212 Cov.: 0 AF XY: 0.766 AC XY: 43855 AN XY: 57258

Gnomad4 AFR AF: 0.876

Gnomad4 AMR AF: 0.788

Gnomad4 ASJ AF: 0.826

Gnomad4 EAS AF: 0.903

Gnomad4 SAS AF: 0.791

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.709

Gnomad4 OTH AF: 0.766

Alfa AF: 0.0450 Hom.: 7

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 17 Benign:2

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Apr 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 04, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71815788; hg19: chr6-170871037;