chr6-170561952-A-G

Variant names:

• chr6-170561952-A-G
• rs55736770
• NM_003194.5:c.216A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_003194.5(TBP):​c.216A>G​(p.Gln72Gln) 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 (★★).

• 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:6
• Conservation: PhyloP100: -0.0240
• Publications: 10 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: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 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 Benign/Likely_benign. ClinVar VariationId is 130558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.024 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.216A>G	p.Gln72Gln	synonymous_variant	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.156A>G	p.Gln52Gln	synonymous_variant	Exon 2 of 7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.216A>G	p.Gln72Gln	synonymous_variant	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 9072 AN: 21320 Hom.: 397 Cov.: 0

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

GnomAD2 exomes AF: 0.0256 AC: 3139 AN: 122506 AF XY: 0.0246

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 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

African (AFR) AF: 0.201 AC: 455 AN: 2264

American (AMR) AF: 0.140 AC: 775 AN: 5546

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 966 AN: 3496

East Asian (EAS) AF: 0.131 AC: 107 AN: 816

South Asian (SAS) AF: 0.161 AC: 1351 AN: 8408

European-Finnish (FIN) AF: 0.341 AC: 2834 AN: 8320

Middle Eastern (MID) AF: 0.124 AC: 47 AN: 378

European-Non Finnish (NFE) AF: 0.217 AC: 31679 AN: 145772

Other (OTH) AF: 0.277 AC: 2144 AN: 7754

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.418 AC: 990 AN: 2368

American (AMR) AF: 0.423 AC: 729 AN: 1724

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 189 AN: 450

East Asian (EAS) AF: 0.108 AC: 8 AN: 74

South Asian (SAS) AF: 0.376 AC: 109 AN: 290

European-Finnish (FIN) AF: 0.418 AC: 731 AN: 1750

Middle Eastern (MID) AF: 0.344 AC: 11 AN: 32

European-Non Finnish (NFE) AF: 0.435 AC: 6162 AN: 14166

Other (OTH) AF: 0.408 AC: 98 AN: 240

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 17 Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 09, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.4
DANN	Benign	0.17
PhyloP100		-0.024
Mutation Taster		=99/1	polymorphism (auto)

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