ENST00000437147.8:n.*247C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000437147.8(TAF1):n.*247C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 326,523 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000033 ( 0 hom. 1 hem. )

Consequence

TAF1
ENST00000437147.8 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:2

Conservation

PhyloP100: -4.11

Publications

3 publications found

Variant links:

Genes affected

TAF1 (HGNC:11535): (TATA-box binding protein associated factor 1) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is the basal transcription factor 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 the largest subunit of TFIID. This subunit binds to core promoter sequences encompassing the transcription start site. It also binds to activators and other transcriptional regulators, and these interactions affect the rate of transcription initiation. This subunit contains two independent protein kinase domains at the N- and C-terminals, but also possesses acetyltransferase activity and can act as a ubiquitin-activating/conjugating enzyme. Mutations in this gene result in Dystonia 3, torsion, X-linked, a dystonia-parkinsonism disorder. Alternative splicing of this gene results in multiple transcript variants. This gene is part of a complex transcription unit (TAF1/DYT3), wherein some transcript variants share exons with TAF1 as well as additional downstream DYT3 exons. [provided by RefSeq, Oct 2013]

TAF1 links:

SOCS6P1 (HGNC:54990): (SOCS6 pseudogene 1)

SOCS6P1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
TAF1	NR_104387.2 link	n.5776C>T	non_coding_transcript_exon_variant	Exon 40 of 40
TAF1	NR_104388.2 link	n.5767C>T	non_coding_transcript_exon_variant	Exon 40 of 40
TAF1	NR_104389.2 link	n.5674C>T	non_coding_transcript_exon_variant	Exon 39 of 39

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
TAF1	ENST00000437147.8 link	n.*247C>T	non_coding_transcript_exon_variant	Exon 14 of 14	1	ENSP00000406517.4	H7C2K9
TAF1	ENST00000462588.5 link	n.*247C>T	non_coding_transcript_exon_variant	Exon 11 of 11	1	ENSP00000508350.1	A0A804HLH3
TAF1	ENST00000467309.5 link	n.*363C>T	non_coding_transcript_exon_variant	Exon 5 of 6	1	ENSP00000507353.1	A0A804HJ48

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112177

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000327

AC:

AN:

214346

Hom.:

Cov.:

AF XY:

0.0000120

AC XY:

AN XY:

83302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6785

American (AMR)

AF:

0.00

AC:

AN:

21033

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7819

East Asian (EAS)

AF:

0.00

AC:

AN:

6590

South Asian (SAS)

AF:

0.00

AC:

AN:

34613

European-Finnish (FIN)

AF:

0.000205

AC:

AN:

9744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2045

European-Non Finnish (NFE)

AF:

0.0000260

AC:

AN:

115264

Other (OTH)

AF:

0.000191

AC:

AN:

10453

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112177

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34325

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30864

American (AMR)

AF:

0.00

AC:

AN:

10600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.000279

AC:

AN:

3582

South Asian (SAS)

AF:

0.00

AC:

AN:

2701

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6073

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53260

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

X-linked dystonia-parkinsonism

Pathogenic:1Uncertain:1

Oct 18, 2012

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Jan 26, 2024

3billion

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Predicted Consequence/Location: non_coding_transcript_exon_variant The variant has been reported to be associated with TAF1 related disorder (ClinVar ID: VCV000021011). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

TAF1-related disorder

Uncertain:1

Jan 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TAF1 c.*65739C>T variant is located in the 3' untranslated region. This variant occurs in a post-coding region of the TAF1 gene and is alternatively known as n.5894C>T (NR_104387.1). This variant has been previously reported in the literature as c.94C>T (p.Arg32Cys) using nomenclature that no longer conforms to current naming conventions (Locus AJ549245.1), and it is often referred to in the literature as DSC3 or the Lubag variant (https://www.ncbi.nlm.nih.gov/books/NBK1489/; Nolte et al. 2003. PubMed ID: 12928496). The DSC3 variant is located within a cluster of five alternative exons (denoted as exons d1-d5) located downstream of the conserved TAF1 exons (exons 1-38) (Herzfeld et al. 2012. PubMed ID: 23184149). Transcript analysis has shown that the exon containing DSC3 can be alternatively spliced onto TAF1 exons 1-37 (Nolte et al. 2003. PubMed ID: 12928496) or can be expressed as a smaller transcript independent of the of TAF1 exons 1-38 (Herzfeld et al. 2012. PubMed ID: 23184149). In a functional study, Herzfeld et al. showed that TAF1 constructs containing DSC3 led to an overall decrease in gene expression (Herzfeld et al. 2013. PubMed ID: 23184149). The DSC3 variant has also been described as one of the seven genetic variants within a haplotype associated with X-linked dystonia-parkinsonism (XDP) in individuals from Panay Island in the Philippines (Domingo et al. 2015. PubMed ID: 25604858). This haplotype has been observed in all affected individuals and includes five single nucleotide variants, a 48-bp deletion, and a 2,627-bp SINE-VNTR-Alu retrotransposon insertion in intron 32 (Domingo et al. 2015. PubMed ID: 25604858). The DSC3 variant or any of the other variants associated with this haplotype have not been conclusively shown to cause XDP (Domingo et al. 2015. PubMed ID: 25604858) and the molecular details regarding XDP pathogenesis is conflicting and not fully understood (Domingo et al. 2015. PubMed ID: 25604858; Capponi et al. 2021. PubMed ID: 34746789). The DSC3 variant is reported in 0.10% of alleles in individuals of East Asian descent in gnomAD. This variant has been interpreted by one laboratory in the ClinVar database as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/21011/). At this time, the clinical significance of the DSC3 variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.53

(source)

DANN

Benign

0.55

PhyloP100

-4.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over