NM_003194.5:c.213_215dupGCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_003194.5(TBP):c.213_215dupGCA(p.Gln72dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 979,026 control chromosomes in the GnomAD database, including 3,426 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q72Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.061 ( 413 hom., cov: 0)

Exomes 𝑓: 0.046 ( 3013 hom. )

Consequence

TBP
NM_003194.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.40

Publications

5 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: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003194.5

BP6

Variant 6-170561925-A-ACAG is Benign according to our data. Variant chr6-170561925-A-ACAG is described in ClinVar as Benign. ClinVar VariationId is 1221615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

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.213_215dupGCA	p.Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.153_155dupGCA	p.Gln52dup	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.213_215dupGCA	p.Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
TBP	ENST00000230354.10	TSL:1	c.213_215dupGCA	p.Gln72dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
TBP	ENST00000421512.5	TSL:1	c.213_215dupGCA	p.Gln72dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes

AF:

0.0605

AC:

7697

AN:

127140

Hom.:

412

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0419

Gnomad AMI

AF:

0.250

Gnomad AMR

AF:

0.0523

Gnomad ASJ

AF:

0.0350

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.0760

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.100

Gnomad NFE

AF:

0.0662

Gnomad OTH

AF:

0.0593

GnomAD4 exome

AF:

0.0459

AC:

39115

AN:

851790

Hom.:

3013

Cov.:

AF XY:

0.0464

AC XY:

20454

AN XY:

441252

show subpopulations

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

African (AFR)

AF:

0.0458

AC:

868

AN:

18942

American (AMR)

AF:

0.0444

AC:

1672

AN:

37618

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

585

AN:

21606

East Asian (EAS)

AF:

0.0398

AC:

1360

AN:

34196

South Asian (SAS)

AF:

0.0599

AC:

4081

AN:

68174

European-Finnish (FIN)

AF:

0.0893

AC:

3772

AN:

42232

Middle Eastern (MID)

AF:

0.0590

AC:

207

AN:

3506

European-Non Finnish (NFE)

AF:

0.0421

AC:

24677

AN:

585876

Other (OTH)

AF:

0.0478

AC:

1893

AN:

39640

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

1710

3420

5129

6839

8549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.0606

AC:

7713

AN:

127236

Hom.:

413

Cov.:

AF XY:

0.0633

AC XY:

3817

AN XY:

60316

show subpopulations

African (AFR)

AF:

0.0423

AC:

1405

AN:

33204

American (AMR)

AF:

0.0524

AC:

620

AN:

11824

Ashkenazi Jewish (ASJ)

AF:

0.0350

AC:

111

AN:

3172

East Asian (EAS)

AF:

0.0234

AC:

AN:

4066

South Asian (SAS)

AF:

0.0754

AC:

234

AN:

3104

European-Finnish (FIN)

AF:

0.109

AC:

871

AN:

7958

Middle Eastern (MID)

AF:

0.108

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.0662

AC:

4051

AN:

61210

Other (OTH)

AF:

0.0587

AC:

AN:

1636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

311

622

932

1243

1554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0658

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=60/40

polymorphism (auto)

(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