chr6-170561966-AGCAGCAGCAGCAG-A

Position:

• chr6-170561966-AGCAGCAGCAGCAG-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_003194.5(TBP):​c.231_243del​(p.Gln77HisfsTer63) variant causes a frameshift change. The variant allele was found at a frequency of 0.0081 in 1,275,690 control chromosomes in the GnomAD database, including 82 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars). 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 0.015 (21 hom., cov: 25)
  • Exomes 𝑓: 0.0072 (61 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 5.03

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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 6-170561966-AGCAGCAGCAGCAG-A is Benign according to our data. Variant chr6-170561966-AGCAGCAGCAGCAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1299293.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-170561966-AGCAGCAGCAGCAG-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2145/141512) while in subpopulation NFE AF= 0.0161 (1046/64894). AF 95% confidence interval is 0.0153. There are 21 homozygotes in gnomad4. There are 1001 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBP	NM_003194.5	c.231_243del	p.Gln77HisfsTer63	frameshift_variant	3/8	ENST00000392092.7
TBP	NM_001172085.2	c.171_183del	p.Gln57HisfsTer63	frameshift_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBP	ENST00000392092.7	c.231_243del	p.Gln77HisfsTer63	frameshift_variant	3/8	1	NM_003194.5	P2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2141 AN: 141408 Hom.: 21 Cov.: 25

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00561

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.0171

GnomAD4 exome AF: 0.00722 AC: 8188 AN: 1134178 Hom.: 61 AF XY: 0.00781 AC XY: 4433 AN XY: 567666

Gnomad4 AFR exome AF: 0.00950

Gnomad4 AMR exome AF: 0.00782

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.0190

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.00653

Gnomad4 NFE exome AF: 0.00575

Gnomad4 OTH exome AF: 0.00925

GnomAD4 genome AF: 0.0152 AC: 2145 AN: 141512 Hom.: 21 Cov.: 25 AF XY: 0.0146 AC XY: 1001 AN XY: 68760

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.0136

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.00561

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.0169

Alfa AF: 0.0228 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771725566; hg19: chr6-170871054;