6-170561958-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_003194.5(TBP):c.222A>G(p.Gln74=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0642 in 142,038 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.064 (429 hom., cov: 26)
  • Exomes 𝑓: 0.033 (1010 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.12

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-170561958-A-G is Benign according to our data. Variant chr6-170561958-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2590300.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-170561958-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBP	NM_003194.5	c.222A>G	p.Gln74=	synonymous_variant	3/8	ENST00000392092.7
TBP	NM_001172085.2	c.162A>G	p.Gln54=	synonymous_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBP	ENST00000392092.7	c.222A>G	p.Gln74=	synonymous_variant	3/8	1	NM_003194.5	P2

Frequencies

GnomAD3 genomes AF: 0.0643 AC: 9120 AN: 141932 Hom.: 430 Cov.: 26

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.0784

Gnomad AMR AF: 0.0511

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.00284

Gnomad SAS AF: 0.0363

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0494

GnomAD3 exomes AF: 0.0238 AC: 3563 AN: 149640 Hom.: 46 AF XY: 0.0230 AC XY: 1874 AN XY: 81604

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.00550

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.00805

Gnomad NFE exome AF: 0.0337

Gnomad OTH exome AF: 0.0390

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0328 AC: 40977 AN: 1249038 Hom.: 1010 Cov.: 103 AF XY: 0.0337 AC XY: 21026 AN XY: 624590

Gnomad4 AFR exome AF: 0.00904

Gnomad4 AMR exome AF: 0.0186

Gnomad4 ASJ exome AF: 0.0351

Gnomad4 EAS exome AF: 0.00203

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.0612

Gnomad4 NFE exome AF: 0.0340

Gnomad4 OTH exome AF: 0.0398

GnomAD4 genome AF: 0.0642 AC: 9116 AN: 142038 Hom.: 429 Cov.: 26 AF XY: 0.0611 AC XY: 4241 AN XY: 69420

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.0510

Gnomad4 ASJ AF: 0.0527

Gnomad4 EAS AF: 0.00285

Gnomad4 SAS AF: 0.0357

Gnomad4 FIN AF: 0.0744

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.0489

Alfa AF: 0.0459 Hom.: 39

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.0
Dann	Benign	0.25

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: rs62430309; hg19: chr6-170871046; COSMIC: COSV57830538;