NM_003194.5:c.216_230delACAGCAACAGCAGCA

Variant names:

• chr6-170561943-GCAGCAGCAACAGCAA-G
• rs770152507
• NM_003194.5:c.216_230delACAGCAACAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP3 BP6_Moderate BS2_Supporting

The NM_003194.5(TBP):​c.216_230delACAGCAACAGCAGCA​(p.Gln73_Gln77del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,579,568 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. Q72Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000069 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.76
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561943-GCAGCAGCAACAGCAA-G is Benign according to our data. Variant chr6-170561943-GCAGCAGCAACAGCAA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2657158.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 9 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.216_230delACAGCAACAGCAGCA	p.Gln73_Gln77del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.156_170delACAGCAACAGCAGCA	p.Gln53_Gln57del	disruptive_inframe_deletion	Exon 2 of 7	NP_001165556.1	P20226-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.216_230delACAGCAACAGCAGCA	p.Gln73_Gln77del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.216_230delACAGCAACAGCAGCA	p.Gln73_Gln77del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.216_230delACAGCAACAGCAGCA	p.Gln73_Gln77del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.0000693 AC: 9 AN: 129792 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000349

Gnomad EAS AF: 0.00133

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000903 AC: 22 AN: 243504 AF XY: 0.0000907

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000407 AC: 59 AN: 1449708 Hom.: 1 AF XY: 0.0000444 AC XY: 32 AN XY: 721264

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

African (AFR) AF: 0.0000600 AC: 2 AN: 33306

American (AMR) AF: 0.00 AC: 0 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105430

Other (OTH) AF: 0.00 AC: 0 AN: 59944

⚠️ 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.

GnomAD4 genome AF: 0.0000693 AC: 9 AN: 129860 Hom.: 0 Cov.: 0 AF XY: 0.0000789 AC XY: 5 AN XY: 63388

African (AFR) AF: 0.0000699 AC: 2 AN: 28624

American (AMR) AF: 0.00 AC: 0 AN: 13218

Ashkenazi Jewish (ASJ) AF: 0.000349 AC: 1 AN: 2866

East Asian (EAS) AF: 0.00133 AC: 6 AN: 4518

South Asian (SAS) AF: 0.00 AC: 0 AN: 4274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63406

Other (OTH) AF: 0.00 AC: 0 AN: 1822

Alfa AF: 0.0212 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=170/30	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs770152507; hg19: chr6-170871031;