NM_003194.5:c.222A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003194.5(TBP):c.222A>G(p.Gln74Gln) 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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.12

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
TBP	NM_003194.5 link	c.222A>G	p.Gln74Gln	synonymous_variant	Exon 3 of 8	ENST00000392092.7	NP_003185.1	P20226-1Q32MN7
TBP	NM_001172085.2 link	c.162A>G	p.Gln54Gln	synonymous_variant	Exon 2 of 7		NP_001165556.1	P20226-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7 link	c.222A>G	p.Gln74Gln	synonymous_variant	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2		P20226-1

Frequencies

GnomAD3 genomes

AF:

0.0643

AC:

9120

AN:

141932

Hom.:

430

Cov.:

show subpopulations

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.:

AF XY:

0.0230

AC XY:

1874

AN XY:

81604

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0611

AC XY:

4241

AN XY:

69420

show subpopulations

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.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Aug 02, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over