chr6-170561958-A-ACAG

Variant names:

• chr6-170561958-A-ACAG
• rs752404282
• NM_003194.5:c.279_281dupGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_003194.5(TBP):​c.279_281dupGCA​(p.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 0.0166 in 143,480 control chromosomes in the GnomAD database, including 39 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (39 hom., cov: 24)
  • Exomes 𝑓: 0.022 (2508 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 4 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: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2378/143480) while in subpopulation NFE AF = 0.02 (1278/63758). AF 95% confidence interval is 0.0191. There are 39 homozygotes in GnomAd4. There are 1097 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2378 AD gene.

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.279_281dupGCA	p.Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.219_221dupGCA	p.Gln74dup	disruptive_inframe_insertion	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.279_281dupGCA	p.Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.279_281dupGCA	p.Gln94dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.279_281dupGCA	p.Gln94dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2372 AN: 143374 Hom.: 39 Cov.: 24

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00368

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.0117

Gnomad FIN AF: 0.0110

Gnomad MID AF: 0.0345

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0180 AC: 2687 AN: 149640 AF XY: 0.0176

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0197

Gnomad FIN exome AF: 0.00502

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0284

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0220 AC: 27715 AN: 1261082 Hom.: 2508 Cov.: 0 AF XY: 0.0215 AC XY: 13546 AN XY: 630374

African (AFR) AF: 0.0164 AC: 471 AN: 28772

American (AMR) AF: 0.0179 AC: 749 AN: 41882

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 280 AN: 23726

East Asian (EAS) AF: 0.0137 AC: 527 AN: 38406

South Asian (SAS) AF: 0.0187 AC: 1524 AN: 81684

European-Finnish (FIN) AF: 0.00947 AC: 440 AN: 46472

Middle Eastern (MID) AF: 0.0226 AC: 112 AN: 4952

European-Non Finnish (NFE) AF: 0.0239 AC: 22529 AN: 941312

Other (OTH) AF: 0.0201 AC: 1083 AN: 53876

GnomAD4 genome AF: 0.0166 AC: 2378 AN: 143480 Hom.: 39 Cov.: 24 AF XY: 0.0157 AC XY: 1097 AN XY: 70058

African (AFR) AF: 0.0135 AC: 531 AN: 39240

American (AMR) AF: 0.0183 AC: 268 AN: 14664

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 33 AN: 3200

East Asian (EAS) AF: 0.0120 AC: 59 AN: 4916

South Asian (SAS) AF: 0.0117 AC: 54 AN: 4628

European-Finnish (FIN) AF: 0.0110 AC: 110 AN: 9992

Middle Eastern (MID) AF: 0.0373 AC: 10 AN: 268

European-Non Finnish (NFE) AF: 0.0200 AC: 1278 AN: 63758

Other (OTH) AF: 0.0160 AC: 32 AN: 1998

Alfa AF: 0.00887 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=54/46	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs752404282; hg19: chr6-170871046; COSMIC: COSV106052917;