6-170561958-ACAG-A

Position:

• chr6-170561958-ACAG-A

Variant summary

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

The NM_003194.5(TBP):​c.279_281del​(p.Gln95del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 143,364 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. Q75Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 21)
  • Exomes 𝑓: 0.0057 (48 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 2.36

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 6-170561958-ACAG-A is Benign according to our data. Variant chr6-170561958-ACAG-A is described in ClinVar as [Benign]. Clinvar id is 599435.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-170561958-ACAG-A is described in Lovd as [Benign]. Variant chr6-170561958-ACAG-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.279_281del	p.Gln95del	inframe_deletion	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.219_221del	p.Gln75del	inframe_deletion	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.279_281del	p.Gln95del	inframe_deletion	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 577 AN: 143258 Hom.: 4 Cov.: 21

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00563

Gnomad EAS AF: 0.00264

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.000501

Gnomad MID AF: 0.00345

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00405

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00574 AC: 7231 AN: 1259444 Hom.: 48 AF XY: 0.00532 AC XY: 3351 AN XY: 629640

Gnomad4 AFR exome AF: 0.00306

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.00371

Gnomad4 EAS exome AF: 0.00190

Gnomad4 SAS exome AF: 0.00171

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00675

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.00403 AC: 578 AN: 143364 Hom.: 4 Cov.: 21 AF XY: 0.00396 AC XY: 277 AN XY: 70014

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.00293

Gnomad4 ASJ AF: 0.00563

Gnomad4 EAS AF: 0.00265

Gnomad4 SAS AF: 0.00216

Gnomad4 FIN AF: 0.000501

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00401

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 20, 2017	Normal variation in repetative sequence -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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: rs752404282; hg19: chr6-170871046;