chr6-170561958-ACAG-A

Variant names:

• chr6-170561958-ACAG-A
• rs752404282
• NM_003194.5:c.279_281delGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_003194.5(TBP):​c.279_281delGCA​(p.Gln94del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 143,364 control chromosomes in the GnomAD database, including 4 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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 21)
  • Exomes 𝑓: 0.0057 (48 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBP NM_003194.5 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.36
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003194.5
• BP6: Variant 6-170561958-ACAG-A is Benign according to our data. Variant chr6-170561958-ACAG-A is described in ClinVar as Benign. ClinVar VariationId is 599435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.279_281delGCA	p.Gln94del	disruptive_inframe_deletion	Exon 3 of 8	NP_003185.1	P20226-1
	TBP	NM_001172085.2		c.219_221delGCA	p.Gln74del	disruptive_inframe_deletion	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.279_281delGCA	p.Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000375942.2	P20226-1
	TBP	ENST00000230354.10	TSL:1	c.279_281delGCA	p.Gln94del	disruptive_inframe_deletion	Exon 3 of 8	ENSP00000230354.5	P20226-1
	TBP	ENST00000421512.5	TSL:1	c.279_281delGCA	p.Gln94del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000400008.1	Q7Z6S5

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 577 AN: 143258 Hom.: 4 Cov.: 21

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00563

Gnomad EAS AF: 0.00264

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.000501

Gnomad MID AF: 0.00345

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00405

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00574 AC: 7231 AN: 1259444 Hom.: 48 AF XY: 0.00532 AC XY: 3351 AN XY: 629640

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

African (AFR) AF: 0.00306 AC: 88 AN: 28758

American (AMR) AF: 0.00328 AC: 137 AN: 41816

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 88 AN: 23710

East Asian (EAS) AF: 0.00190 AC: 73 AN: 38382

South Asian (SAS) AF: 0.00171 AC: 140 AN: 81634

European-Finnish (FIN) AF: 0.00131 AC: 61 AN: 46390

Middle Eastern (MID) AF: 0.00323 AC: 16 AN: 4948

European-Non Finnish (NFE) AF: 0.00675 AC: 6347 AN: 940046

Other (OTH) AF: 0.00523 AC: 281 AN: 53760

⚠️ 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: 0.00403 AC: 578 AN: 143364 Hom.: 4 Cov.: 21 AF XY: 0.00396 AC XY: 277 AN XY: 70014

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

African (AFR) AF: 0.00390 AC: 153 AN: 39198

American (AMR) AF: 0.00293 AC: 43 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 18 AN: 3196

East Asian (EAS) AF: 0.00265 AC: 13 AN: 4914

South Asian (SAS) AF: 0.00216 AC: 10 AN: 4628

European-Finnish (FIN) AF: 0.000501 AC: 5 AN: 9990

Middle Eastern (MID) AF: 0.00373 AC: 1 AN: 268

European-Non Finnish (NFE) AF: 0.00513 AC: 327 AN: 63706

Other (OTH) AF: 0.00401 AC: 8 AN: 1996

⚠️ 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: 0.00 Hom.: 4

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=44/56	disease causing

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: rs752404282; hg19: chr6-170871046; COSMIC: COSV57830794;