X-71518692-CTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chrX-71518692-C-CTTTTTTTTTTTTTT
• rs41486346
• ENST00000437147.8:n.1359-9850_1359-9849insTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000437147.8(TAF1):​n.1359-9850_1359-9849insTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 0 hem., cov: 19)
  • Failed GnomAD Quality Control
• Consequence: TAF1 ENST00000437147.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked, syndromic 33

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• X-linked dystonia-parkinsonism

  Inheritance: XL, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000437147.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	NR_104387.2		n.5520-9842_5520-9829dupTTTTTTTTTTTTTT		intron	N/A
	TAF1	NR_104388.2		n.5511-9842_5511-9829dupTTTTTTTTTTTTTT		intron	N/A
	TAF1	NR_104389.2		n.5418-9842_5418-9829dupTTTTTTTTTTTTTT		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	ENST00000437147.8	TSL:1	n.1359-9850_1359-9849insTTTTTTTTTTTTTT		intron	N/A	ENSP00000406517.4
	TAF1	ENST00000462588.5	TSL:1	n.999-9850_999-9849insTTTTTTTTTTTTTT		intron	N/A	ENSP00000508350.1
	TAF1	ENST00000467309.5	TSL:1	n.*107-9850_*107-9849insTTTTTTTTTTTTTT		intron	N/A	ENSP00000507353.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 102 AN: 79159 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000713

Gnomad AMI AF: 0.00189

Gnomad AMR AF: 0.00155

Gnomad ASJ AF: 0.00194

Gnomad EAS AF: 0.000413

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000389

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00129 AC: 102 AN: 79159 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 18547

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

African (AFR) AF: 0.000713 AC: 15 AN: 21026

American (AMR) AF: 0.00155 AC: 11 AN: 7091

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 4 AN: 2065

East Asian (EAS) AF: 0.000413 AC: 1 AN: 2422

South Asian (SAS) AF: 0.00 AC: 0 AN: 1590

European-Finnish (FIN) AF: 0.000389 AC: 1 AN: 2574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 168

European-Non Finnish (NFE) AF: 0.00170 AC: 69 AN: 40666

Other (OTH) AF: 0.00 AC: 0 AN: 1029

⚠️ 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: 0.00155 Hom.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

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

Other links and lift over

dbSNP: rs41486346; hg19: chrX-70738542;