NM_003194.5:c.*697G>A

Variant names:

• chr6-170572962-G-A
• rs6937840
• NM_003194.5:c.*697G>A

Variant summary

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

The NM_003194.5(TBP):​c.*697G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 152,126 control chromosomes in the GnomAD database, including 22,782 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 0.54 (22782 hom., cov: 33)
  • Exomes 𝑓: 0.38 (0 hom.)
• Consequence: TBP NM_003194.5 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.*697G>A		downstream_gene_variant		ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.*697G>A		downstream_gene_variant			NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.*697G>A		downstream_gene_variant		1	NM_003194.5	ENSP00000375942.2

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82429 AN: 152000 Hom.: 22745 Cov.: 33

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.375 AC: 3 AN: 8 Hom.: 0 AF XY: 0.375 AC XY: 3 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.542 AC: 82511 AN: 152118 Hom.: 22782 Cov.: 33 AF XY: 0.540 AC XY: 40179 AN XY: 74368

African (AFR) AF: 0.625 AC: 25926 AN: 41482

American (AMR) AF: 0.470 AC: 7184 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1731 AN: 3472

East Asian (EAS) AF: 0.785 AC: 4052 AN: 5160

South Asian (SAS) AF: 0.481 AC: 2324 AN: 4832

European-Finnish (FIN) AF: 0.486 AC: 5139 AN: 10574

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34247 AN: 67986

Other (OTH) AF: 0.541 AC: 1145 AN: 2116

Alfa AF: 0.530 Hom.: 2791

Bravo AF: 0.552

Asia WGS AF: 0.628 AC: 2184 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0080
DANN	Benign	0.19
PhyloP100		-1.5
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs6937840; hg19: chr6-170882050;