6-170561958-A-G

Variant names:

• chr6-170561958-A-G
• rs62430309
• NM_003194.5:c.222A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.12
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 2590300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003194.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	NM_003194.5	MANE Select	c.222A>G	p.Gln74Gln	synonymous	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.162A>G	p.Gln54Gln	synonymous	Exon 2 of 7	NP_001165556.1	P20226-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBP	ENST00000392092.7	TSL:1 MANE Select	c.222A>G	p.Gln74Gln	synonymous	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.222A>G	p.Gln74Gln	synonymous	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.222A>G	p.Gln74Gln	synonymous	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

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

GnomAD2 exomes AF: 0.0238 AC: 3563 AN: 149640 AF XY: 0.0230

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00904 AC: 260 AN: 28754

American (AMR) AF: 0.0186 AC: 780 AN: 41836

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 831 AN: 23662

East Asian (EAS) AF: 0.00203 AC: 78 AN: 38380

South Asian (SAS) AF: 0.0287 AC: 2343 AN: 81500

European-Finnish (FIN) AF: 0.0612 AC: 2828 AN: 46220

Middle Eastern (MID) AF: 0.0121 AC: 60 AN: 4948

European-Non Finnish (NFE) AF: 0.0340 AC: 31669 AN: 930226

Other (OTH) AF: 0.0398 AC: 2128 AN: 53512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0169 AC: 661 AN: 39128

American (AMR) AF: 0.0510 AC: 742 AN: 14552

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 167 AN: 3166

East Asian (EAS) AF: 0.00285 AC: 14 AN: 4916

South Asian (SAS) AF: 0.0357 AC: 164 AN: 4596

European-Finnish (FIN) AF: 0.0744 AC: 734 AN: 9866

Middle Eastern (MID) AF: 0.0373 AC: 10 AN: 268

European-Non Finnish (NFE) AF: 0.103 AC: 6464 AN: 62758

Other (OTH) AF: 0.0489 AC: 97 AN: 1984

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0459 Hom.: 39

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.0
DANN	Benign	0.25
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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