rs112083427

Variant names:

• chr6-170561964-G-A
• rs112083427
• NM_003194.5:c.228G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-170561964-G-A
• chr6-170561964-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_003194.5(TBP):​c.228G>A​(p.Gln76Gln) 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. 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 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:2
• Conservation: PhyloP100: 1.02
• Publications: 10 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: Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 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 submission is: [Conflicting_classifications_of_pathogenicity].
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBP	NM_003194.5	c.228G>A	p.Gln76Gln	synonymous_variant	Exon 3 of 8	ENST00000392092.7	NP_003185.1
TBP	NM_001172085.2	c.168G>A	p.Gln56Gln	synonymous_variant	Exon 2 of 7		NP_001165556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBP	ENST00000392092.7	c.228G>A	p.Gln76Gln	synonymous_variant	Exon 3 of 8	1	NM_003194.5	ENSP00000375942.2

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

African (AFR) AF: 0.215 AC: 1611 AN: 7488

American (AMR) AF: 0.457 AC: 6463 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 3063 AN: 8178

East Asian (EAS) AF: 0.443 AC: 6413 AN: 14472

South Asian (SAS) AF: 0.375 AC: 12344 AN: 32932

European-Finnish (FIN) AF: 0.430 AC: 9328 AN: 21694

Middle Eastern (MID) AF: 0.295 AC: 574 AN: 1946

European-Non Finnish (NFE) AF: 0.155 AC: 61641 AN: 396594

Other (OTH) AF: 0.268 AC: 6094 AN: 22714

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

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

African (AFR) AF: 0.126 AC: 4398 AN: 34832

American (AMR) AF: 0.340 AC: 4153 AN: 12208

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 735 AN: 2776

East Asian (EAS) AF: 0.237 AC: 1041 AN: 4396

South Asian (SAS) AF: 0.288 AC: 1054 AN: 3656

European-Finnish (FIN) AF: 0.317 AC: 2714 AN: 8572

Middle Eastern (MID) AF: 0.303 AC: 72 AN: 238

European-Non Finnish (NFE) AF: 0.256 AC: 14111 AN: 55228

Other (OTH) AF: 0.246 AC: 406 AN: 1648

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.0
DANN	Benign	0.33
PhyloP100		1.0
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: rs112083427; hg19: chr6-170871052; COSMIC: COSV57830435;