6-170561957-A-AGC

Variant names:

• chr6-170561957-A-AGC
• rs1290125655
• NM_003194.5:c.221_222insGC

Variant summary

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

The NM_003194.5(TBP):​c.221_222insGC​(p.Gln75HisfsTer70) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,505,438 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: TBP NM_003194.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

ACMG classification

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

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.221_222insGC	p.Gln75HisfsTer70	frameshift	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.161_162insGC	p.Gln55HisfsTer70	frameshift	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.221_222insGC	p.Gln75HisfsTer70	frameshift	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.221_222insGC	p.Gln75HisfsTer70	frameshift	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.221_222insGC	p.Gln75HisfsTer70	frameshift	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.000954 AC: 94 AN: 98502 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000888

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00799

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00455

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.000723

GnomAD2 exomes AF: 0.000247 AC: 60 AN: 242460 AF XY: 0.000235

Gnomad AFR exome AF: 0.000404

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000456

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000229 AC: 322 AN: 1406896 Hom.: 1 Cov.: 103 AF XY: 0.000264 AC XY: 185 AN XY: 700038

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

African (AFR) AF: 0.000520 AC: 17 AN: 32704

American (AMR) AF: 0.000137 AC: 6 AN: 43758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25262

East Asian (EAS) AF: 0.00420 AC: 165 AN: 39240

South Asian (SAS) AF: 0.000671 AC: 56 AN: 83472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.0000533 AC: 57 AN: 1068696

Other (OTH) AF: 0.000361 AC: 21 AN: 58174

⚠️ 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: 0.000984 AC: 97 AN: 98542 Hom.: 0 Cov.: 26 AF XY: 0.000967 AC XY: 47 AN XY: 48592

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

African (AFR) AF: 0.00489 AC: 41 AN: 8380

American (AMR) AF: 0.0000886 AC: 1 AN: 11282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2210

East Asian (EAS) AF: 0.00801 AC: 33 AN: 4120

South Asian (SAS) AF: 0.00126 AC: 5 AN: 3966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9262

Middle Eastern (MID) AF: 0.00485 AC: 1 AN: 206

European-Non Finnish (NFE) AF: 0.000264 AC: 15 AN: 56884

Other (OTH) AF: 0.000711 AC: 1 AN: 1406

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000457 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spinocerebellar ataxia type 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=197/3	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs1290125655; hg19: chr6-170871045;