6-170561952-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003194.5(TBP):c.216A>G(p.Gln72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. QQ72Q?) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.43 (396 hom., cov: 0)
  • Exomes 𝑓: 0.22 (2037 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0240

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 6-170561952-A-G is Benign according to our data. Variant chr6-170561952-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-170561952-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.024 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 14 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBP	NM_003194.5	c.216A>G	p.Gln72=	synonymous_variant	3/8	ENST00000392092.7
TBP	NM_001172085.2	c.156A>G	p.Gln52=	synonymous_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBP	ENST00000392092.7	c.216A>G	p.Gln72=	synonymous_variant	3/8	1	NM_003194.5	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 9072 AN: 21320 Hom.: 397 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.405

GnomAD3 exomes AF: 0.0256 AC: 3139 AN: 122506 Hom.: 14 AF XY: 0.0246 AC XY: 1610 AN XY: 65532

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0205

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.00922

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0358

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.221 AC: 40358 AN: 182754 Hom.: 2037 Cov.: 0 AF XY: 0.227 AC XY: 20689 AN XY: 91106

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.276

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.341

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.426 AC: 9067 AN: 21308 Hom.: 396 Cov.: 0 AF XY: 0.421 AC XY: 4229 AN XY: 10042

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.420

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.418

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.408

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 17 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.4
Dann	Benign	0.17

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: rs55736770; hg19: chr6-170871040; COSMIC: COSV57830532;