Variant 6-170561957-A-AGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_003194.5(TBP):c.221_222insGC(p.Gln75HisfsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,505,438 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

TBP
NM_003194.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5 linkuse as main transcript	c.221_222insGC	p.Gln75HisfsTer70	frameshift_variant	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2 linkuse as main transcript	c.161_162insGC	p.Gln55HisfsTer70	frameshift_variant	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7 linkuse as main transcript	c.221_222insGC	p.Gln75HisfsTer70	frameshift_variant	3/8	1	NM_003194.5	ENSP00000375942	P2	P20226-1

Frequencies

GnomAD3 genomes

AF:

0.000954

AC:

AN:

98502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00455

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000888

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00799

Gnomad SAS

AF:

0.00126

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00455

Gnomad NFE

AF:

0.000264

Gnomad OTH

AF:

0.000723

GnomAD4 exome

AF:

0.000229

AC:

322

AN:

1406896

Hom.:

Cov.:

103

AF XY:

0.000264

AC XY:

185

AN XY:

700038

show subpopulations

Gnomad4 AFR exome

AF:

0.000520

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00420

Gnomad4 SAS exome

AF:

0.000671

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000533

Gnomad4 OTH exome

AF:

0.000361

GnomAD4 genome

AF:

0.000984

AC:

AN:

98542

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

48592

show subpopulations

Gnomad4 AFR

AF:

0.00489

Gnomad4 AMR

AF:

0.0000886

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00801

Gnomad4 SAS

AF:

0.00126

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000264

Gnomad4 OTH

AF:

0.000711

Alfa

AF:

0.000457

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 17

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over