chrX-71504741-C-CAAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant names:

• chrX-71504741-C-CAAAAAAAAAAAAAAAAAAAAAAAAAAA
• rs41370846
• ENST00000437147.8:n.1359-23801_1359-23800insAAAAAAAAAAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The ENST00000437147.8(TAF1):​n.1359-23801_1359-23800insAAAAAAAAAAAAAAAAAAAAAAAAAAA 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 0.0044 (0 hom., 0 hem., cov: 9)
• Consequence: TAF1 ENST00000437147.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• 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: G2P, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• X-linked dystonia-parkinsonism

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00438 (25/5712) while in subpopulation NFE AF = 0.0059 (17/2883). AF 95% confidence interval is 0.00376. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 9. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	NR_104387.2		n.5520-23795_5520-23769dupAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A
	TAF1	NR_104388.2		n.5511-23795_5511-23769dupAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A
	TAF1	NR_104389.2		n.5418-23795_5418-23769dupAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	ENST00000437147.8	TSL:1	n.1359-23801_1359-23800insAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000406517.4	H7C2K9
	TAF1	ENST00000462588.5	TSL:1	n.999-23801_999-23800insAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000508350.1	A0A804HLH3
	TAF1	ENST00000467309.5	TSL:1	n.*106+19748_*106+19749insAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A	ENSP00000507353.1	A0A804HJ48

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 25 AN: 5712 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00554

Gnomad ASJ AF: 0.00535

Gnomad EAS AF: 0.00485

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00589

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.00438 AC: 25 AN: 5712 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 208

African (AFR) AF: 0.00213 AC: 4 AN: 1881

American (AMR) AF: 0.00554 AC: 2 AN: 361

Ashkenazi Jewish (ASJ) AF: 0.00535 AC: 1 AN: 187

East Asian (EAS) AF: 0.00485 AC: 1 AN: 206

South Asian (SAS) AF: 0.00 AC: 0 AN: 43

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 64

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00590 AC: 17 AN: 2883

Other (OTH) AF: 0.00 AC: 0 AN: 60

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22

Splicing

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

Other links and lift over

dbSNP: rs41370846; hg19: chrX-70724591;