chr6-170561958-A-ACAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP5_ModerateBP3BS2_Supporting

The NM_003194.5(TBP):c.264_281dupGCAGCAGCAGCAGCAGCA(p.Gln89_Gln94dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000868 in 1,405,176 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

TBP
NM_003194.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.290

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 17
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

TBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 6-170561958-A-ACAGCAGCAGCAGCAGCAG is Pathogenic according to our data. Variant chr6-170561958-A-ACAGCAGCAGCAGCAGCAG is described in ClinVar as Pathogenic. ClinVar VariationId is 2576597.Status of the report is criteria_provided_single_submitter, 1 stars.

BP3

Nonframeshift variant in repetitive region in NM_003194.5

BS2

High AC in GnomAd4 at 26 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003194.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.264_281dupGCAGCAGCAGCAGCAGCA	p.Gln89_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.204_221dupGCAGCAGCAGCAGCAGCA	p.Gln69_Gln74dup	disruptive_inframe_insertion	Exon 2 of 7	NP_001165556.1	P20226-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBP	ENST00000392092.7	TSL:1 MANE Select	c.264_281dupGCAGCAGCAGCAGCAGCA	p.Gln89_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
TBP	ENST00000230354.10	TSL:1	c.264_281dupGCAGCAGCAGCAGCAGCA	p.Gln89_Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
TBP	ENST00000421512.5	TSL:1	c.264_281dupGCAGCAGCAGCAGCAGCA	p.Gln89_Gln94dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes

AF:

0.000181

AC:

AN:

143372

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000204

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

Gnomad ASJ

AF:

0.000313

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.000432

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000761

AC:

AN:

1261698

Hom.:

Cov.:

AF XY:

0.0000904

AC XY:

AN XY:

630694

show subpopulations

African (AFR)

AF:

0.0000348

AC:

AN:

28776

American (AMR)

AF:

0.000215

AC:

AN:

41894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23728

East Asian (EAS)

AF:

0.000208

AC:

AN:

38406

South Asian (SAS)

AF:

0.000196

AC:

AN:

81726

European-Finnish (FIN)

AF:

0.0000215

AC:

AN:

46476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4954

European-Non Finnish (NFE)

AF:

0.0000531

AC:

AN:

941840

Other (OTH)

AF:

0.000204

AC:

AN:

53898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000181

AC:

AN:

143478

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

70064

show subpopulations

African (AFR)

AF:

0.000204

AC:

AN:

39244

American (AMR)

AF:

0.000136

AC:

AN:

14660

Ashkenazi Jewish (ASJ)

AF:

0.000313

AC:

AN:

3200

East Asian (EAS)

AF:

0.000203

AC:

AN:

4916

South Asian (SAS)

AF:

0.000432

AC:

AN:

4628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000188

AC:

AN:

63756

Other (OTH)

AF:

0.00

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spinocerebellar ataxia type 17 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.29

Mutation Taster

=54/46

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over