NM_003194.5:c.231delG

Variant names:

• chr6-170561966-AG-A
• rs770128377
• NM_003194.5:c.231delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003194.5(TBP):​c.231delG​(p.Gln77HisfsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.093 in 1,036,150 control chromosomes in the GnomAD database, including 3,499 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.14 (1707 hom., cov: 27)
  • Exomes 𝑓: 0.086 (1792 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 2.39
• Publications: 7 publications found

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]

TBP Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 17

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 6-170561966-AG-A is Benign according to our data. Variant chr6-170561966-AG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 3065444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003194.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.231delG	p.Gln77HisfsTer67	frameshift	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.171delG	p.Gln57HisfsTer67	frameshift	Exon 2 of 7	NP_001165556.1	P20226-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.231delG	p.Gln77HisfsTer67	frameshift	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.231delG	p.Gln77HisfsTer67	frameshift	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.231delG	p.Gln77HisfsTer67	frameshift	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 19073 AN: 139944 Hom.: 1705 Cov.: 27

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.129

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.0227 AC: 4178 AN: 184244 AF XY: 0.0210

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.00512

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0863 AC: 77293 AN: 896102 Hom.: 1792 Cov.: 0 AF XY: 0.0931 AC XY: 41824 AN XY: 449306

African (AFR) AF: 0.0581 AC: 1202 AN: 20698

American (AMR) AF: 0.122 AC: 2983 AN: 24360

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 2442 AN: 17302

East Asian (EAS) AF: 0.447 AC: 13961 AN: 31210

South Asian (SAS) AF: 0.178 AC: 9966 AN: 56006

European-Finnish (FIN) AF: 0.0695 AC: 2226 AN: 32008

Middle Eastern (MID) AF: 0.111 AC: 444 AN: 4002

European-Non Finnish (NFE) AF: 0.0592 AC: 39736 AN: 671260

Other (OTH) AF: 0.110 AC: 4333 AN: 39256

GnomAD4 genome AF: 0.136 AC: 19091 AN: 140048 Hom.: 1707 Cov.: 27 AF XY: 0.132 AC XY: 8978 AN XY: 68012

African (AFR) AF: 0.0914 AC: 3341 AN: 36570

American (AMR) AF: 0.131 AC: 1880 AN: 14356

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 621 AN: 3302

East Asian (EAS) AF: 0.492 AC: 2162 AN: 4398

South Asian (SAS) AF: 0.202 AC: 850 AN: 4204

European-Finnish (FIN) AF: 0.0590 AC: 594 AN: 10064

Middle Eastern (MID) AF: 0.129 AC: 36 AN: 280

European-Non Finnish (NFE) AF: 0.143 AC: 9137 AN: 64088

Other (OTH) AF: 0.150 AC: 291 AN: 1934

Alfa AF: 0.0466 Hom.: 36

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 17 (1)
-	-	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=199/1	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs770128377; hg19: chr6-170871054; COSMIC: COSV57830658;