6-170561964-G-A

Position:

• chr6-170561964-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003194.5(TBP):​c.228G>A​(p.Gln76=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 124,342 control chromosomes in the GnomAD database, including 3,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (3093 hom., cov: 21)
  • Exomes 𝑓: 0.21 (1226 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.02

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 6-170561964-G-A is Benign according to our data. Variant chr6-170561964-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130560.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr6-170561964-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBP	NM_003194.5	c.228G>A	p.Gln76=	synonymous_variant	3/8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.168G>A	p.Gln56=	synonymous_variant	2/7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.228G>A	p.Gln76=	synonymous_variant	3/8	1	NM_003194.5	ENSP00000375942	P2

Frequencies

GnomAD3 genomes AF: 0.231 AC: 28752 AN: 124274 Hom.: 3093 Cov.: 21

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.249

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.207 AC: 107531 AN: 520172 Hom.: 1226 Cov.: 20 AF XY: 0.223 AC XY: 57592 AN XY: 258494

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.375

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.231 AC: 28766 AN: 124342 Hom.: 3093 Cov.: 21 AF XY: 0.234 AC XY: 14099 AN XY: 60208

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.246

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.0
DANN	Benign	0.33

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: rs112083427; hg19: chr6-170871052; COSMIC: COSV57830435;