chr6-170561964-G-GCAGCAA

Variant names:

• chr6-170561964-G-GCAGCAA
• rs776458919
• NM_003194.5:c.233_234insACAGCA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_003194.5(TBP):​c.233_234insACAGCA​(p.Gln77_Gln78dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000226 in 883,536 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000079 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000013 (0 hom.)
• Consequence: TBP NM_003194.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• Publications: 2 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: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_003194.5

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.233_234insACAGCA	p.Gln77_Gln78dup	disruptive_inframe_insertion	Exon 3 of 8	NP_003185.1
	TBP	NM_001172085.2		c.173_174insACAGCA	p.Gln57_Gln58dup	disruptive_inframe_insertion	Exon 2 of 7	NP_001165556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.233_234insACAGCA	p.Gln77_Gln78dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000375942.2
	TBP	ENST00000230354.10	TSL:1	c.233_234insACAGCA	p.Gln77_Gln78dup	disruptive_inframe_insertion	Exon 3 of 8	ENSP00000230354.5
	TBP	ENST00000421512.5	TSL:1	c.233_234insACAGCA	p.Gln77_Gln78dup	disruptive_inframe_insertion	Exon 3 of 5	ENSP00000400008.1

Frequencies

GnomAD3 genomes AF: 0.00000787 AC: 1 AN: 127018 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000222

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

GnomAD4 exome AF: 0.00000132 AC: 1 AN: 756450 Hom.: 0 Cov.: 0 AF XY: 0.00000267 AC XY: 1 AN XY: 374038

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

African (AFR) AF: 0.00 AC: 0 AN: 8368

American (AMR) AF: 0.00 AC: 0 AN: 16484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10240

East Asian (EAS) AF: 0.0000661 AC: 1 AN: 15136

South Asian (SAS) AF: 0.00 AC: 0 AN: 41590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 603832

Other (OTH) AF: 0.00 AC: 0 AN: 31010

⚠️ 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: 0.00000787 AC: 1 AN: 127086 Hom.: 0 Cov.: 28 AF XY: 0.0000163 AC XY: 1 AN XY: 61534

African (AFR) AF: 0.00 AC: 0 AN: 35314

American (AMR) AF: 0.00 AC: 0 AN: 12548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2850

East Asian (EAS) AF: 0.000223 AC: 1 AN: 4486

South Asian (SAS) AF: 0.00 AC: 0 AN: 3764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56592

Other (OTH) AF: 0.00 AC: 0 AN: 1684

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=49/51	disease causing

Splicing

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

Other links and lift over

dbSNP: rs776458919; hg19: chr6-170871052;