chr6-170554285-T-C

Variant names:

• chr6-170554285-T-C
• rs2179373
• NM_003194.5:c.-327T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003194.5(TBP):​c.-327T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 152,254 control chromosomes in the GnomAD database, including 6,254 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6250 hom., cov: 33)
  • Exomes 𝑓: 0.32 (4 hom.)
• Consequence: TBP NM_003194.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 12 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.71 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.-327T>C		upstream_gene	N/A	NP_003185.1
	TBP	NM_001172085.2		c.-185T>C		upstream_gene	N/A	NP_001165556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.-327T>C		upstream_gene	N/A	ENSP00000375942.2
	TBP	ENST00000230354.10	TSL:1	c.-330T>C		upstream_gene	N/A	ENSP00000230354.5
	TBP	ENST00000421512.5	TSL:1	c.-327T>C		upstream_gene	N/A	ENSP00000400008.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39511 AN: 152062 Hom.: 6251 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.272

GnomAD4 exome AF: 0.324 AC: 24 AN: 74 Hom.: 4 Cov.: 0 AF XY: 0.280 AC XY: 14 AN XY: 50

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.375 AC: 18 AN: 48

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.260 AC: 39510 AN: 152180 Hom.: 6250 Cov.: 33 AF XY: 0.261 AC XY: 19444 AN XY: 74400

African (AFR) AF: 0.122 AC: 5063 AN: 41538

American (AMR) AF: 0.273 AC: 4182 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3470

East Asian (EAS) AF: 0.729 AC: 3757 AN: 5152

South Asian (SAS) AF: 0.345 AC: 1662 AN: 4824

European-Finnish (FIN) AF: 0.268 AC: 2840 AN: 10598

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20249 AN: 67982

Other (OTH) AF: 0.275 AC: 581 AN: 2116

Alfa AF: 0.268 Hom.: 3084

Bravo AF: 0.261

Asia WGS AF: 0.487 AC: 1691 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.48
DANN	Benign	0.30
PhyloP100		-0.028
PromoterAI		0.014	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2179373; hg19: chr6-170863373;