X-71445298-CAAAAAAAAAA-CAAAAAAAAAAA

Variant names:

• chrX-71445298-C-CA
• rs41356545
• NM_004606.5:c.4754-8852dupA

Variant summary

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

The NM_004606.5(TAF1):​c.4754-8852dupA 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 0.024 (17 hom., 62 hem., cov: 18)
• Consequence: TAF1 NM_004606.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.756
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0241 (881/36487) while in subpopulation NFE AF = 0.0303 (629/20776). AF 95% confidence interval is 0.0283. There are 17 homozygotes in GnomAd4. There are 62 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF1	NM_004606.5	c.4754-8852dupA		intron_variant	Intron 32 of 37	ENST00000423759.6	NP_004597.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF1	ENST00000423759.6	c.4754-8872_4754-8871insA		intron_variant	Intron 32 of 37	5	NM_004606.5	ENSP00000406549.2

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 881 AN: 36479 Hom.: 17 Cov.: 18

Gnomad AFR AF: 0.00829

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00192

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.00616

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

GnomAD4 genome AF: 0.0241 AC: 881 AN: 36487 Hom.: 17 Cov.: 18 AF XY: 0.0114 AC XY: 62 AN XY: 5429

African (AFR) AF: 0.00828 AC: 72 AN: 8699

American (AMR) AF: 0.0138 AC: 38 AN: 2744

Ashkenazi Jewish (ASJ) AF: 0.00192 AC: 2 AN: 1044

East Asian (EAS) AF: 0.0117 AC: 10 AN: 856

South Asian (SAS) AF: 0.00167 AC: 1 AN: 600

European-Finnish (FIN) AF: 0.0951 AC: 87 AN: 915

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 69

European-Non Finnish (NFE) AF: 0.0303 AC: 629 AN: 20776

Other (OTH) AF: 0.00609 AC: 3 AN: 493

Alfa AF: 0.00615 Hom.: 49

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism

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: rs41356545; hg19: chrX-70665148;