chr6-170561966-AG-A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate 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 (★). Synonymous variant affecting the same amino acid position (i.e. Q77Q) has been classified 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: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.39

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 -10 ACMG points.

• BP6: Variant 6-170561966-AG-A is Benign according to our data. Variant chr6-170561966-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 3065444.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-170561966-AG-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.231delG	p.Gln77HisfsTer67	frameshift_variant	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.171delG	p.Gln57HisfsTer67	frameshift_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.231delG	p.Gln77HisfsTer67	frameshift_variant	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

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

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

Gnomad4 AFR exome AF: 0.0581

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.447

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.0695

Gnomad4 NFE exome AF: 0.0592

Gnomad4 OTH exome AF: 0.110

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

Gnomad4 AFR AF: 0.0914

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.492

Gnomad4 SAS AF: 0.202

Gnomad4 FIN AF: 0.0590

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.150

Alfa AF: 0.0466 Hom.: 36

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Parkinson disease, late-onset Other:1

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GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 02-14-2020 by Macrogen. GenomeConnect-Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

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