X-71452109-A-ACC

Variant names:

• chrX-71452109-A-ACC
• rs41443746
• NM_004606.5:c.4754-2051_4754-2050dupCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_004606.5(TAF1):​c.4754-2051_4754-2050dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0021 (1 hom., 11 hem., cov: 15)
• Consequence: TAF1 NM_004606.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (106/50598) while in subpopulation NFE AF = 0.00347 (85/24489). AF 95% confidence interval is 0.00288. There are 1 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 15. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 11 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004606.5. 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
	TAF1	NM_004606.5	MANE Select	c.4754-2051_4754-2050dupCC		intron	N/A	NP_004597.3
	TAF1	NM_001286074.2		c.4754-2051_4754-2050dupCC		intron	N/A	NP_001273003.2
	TAF1	NM_001440852.1		c.4754-2051_4754-2050dupCC		intron	N/A	NP_001427781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	ENST00000423759.6	TSL:5 MANE Select	c.4754-2061_4754-2060insCC		intron	N/A	ENSP00000406549.2	P21675-14
	TAF1	ENST00000373790.9	TSL:1	c.4691-2061_4691-2060insCC		intron	N/A	ENSP00000362895.5	P21675-13
	TAF1	ENST00000437147.8	TSL:1	n.713-2061_713-2060insCC		intron	N/A	ENSP00000406517.4	H7C2K9

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 106 AN: 50606 Hom.: 1 Cov.: 15

Gnomad AFR AF: 0.000609

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00196

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00310

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

GnomAD4 genome AF: 0.00209 AC: 106 AN: 50598 Hom.: 1 Cov.: 15 AF XY: 0.00105 AC XY: 11 AN XY: 10444

African (AFR) AF: 0.000608 AC: 9 AN: 14800

American (AMR) AF: 0.00137 AC: 6 AN: 4385

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1291

East Asian (EAS) AF: 0.00 AC: 0 AN: 1558

South Asian (SAS) AF: 0.00 AC: 0 AN: 986

European-Finnish (FIN) AF: 0.00196 AC: 4 AN: 2046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 72

European-Non Finnish (NFE) AF: 0.00347 AC: 85 AN: 24489

Other (OTH) AF: 0.00307 AC: 2 AN: 651

Alfa AF: 0.00 Hom.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.055

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41443746; hg19: chrX-70671959;