6-170561955-GCAA-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP3 BP6

The NM_003194.5(TBP):c.222_224del(p.Gln95del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,485,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TBP NM_003194.5 inframe_deletion
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.41

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561955-GCAA-G is Benign according to our data. Variant chr6-170561955-GCAA-G is described in ClinVar as [Benign]. Clinvar id is 1050369.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBP	NM_003194.5	c.222_224del	p.Gln95del	inframe_deletion	3/8	ENST00000392092.7
TBP	NM_001172085.2	c.162_164del	p.Gln75del	inframe_deletion	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBP	ENST00000392092.7	c.222_224del	p.Gln95del	inframe_deletion	3/8	1	NM_003194.5	P2

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 17 AN: 60384 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00198

Gnomad AMR AF: 0.000278

Gnomad ASJ AF: 0.000684

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.000384

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000241

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000695 AC: 99 AN: 1425372 Hom.: 0 AF XY: 0.0000748 AC XY: 53 AN XY: 708360

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000717

Gnomad4 OTH exome AF: 0.0000680

GnomAD4 genome AF: 0.000265 AC: 16 AN: 60434 Hom.: 0 Cov.: 26 AF XY: 0.000300 AC XY: 9 AN XY: 29986

Gnomad4 AFR AF: 0.000551

Gnomad4 AMR AF: 0.000277

Gnomad4 ASJ AF: 0.000684

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000384

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000241

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The TBP p.Gln75del variant was not identified in the literature nor was it identified in dbSNP, Cosmic or LOVD 3.0. The variant was identified in ClinVar (classified as benign by Genome Diagnostics Laboratory, University Medical Center Utrecht and DNA and Cytogenetics Diagnostics Unit, Erasmus Medical Center) and in control databases in 3 of 215972 chromosomes at a frequency of 0.000014 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 3 of 97710 chromosomes (freq: 0.000031), but not in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. This variant is an in-frame deletion resulting in the removal of a glutamine (gln) residue at codon 75; this deletion occurs within a CAG repeat region and is within the normal range of 25 to 42 repeats. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1562359513; hg19: chr6-170871043;