X-71366210-A-C

Variant names:

• chrX-71366210-A-C
• rs7055342
• ENST00000715246.1:c.-105A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000715246.1(TAF1):​c.-105A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (656 hom., 1239 hem., cov: 0)
  • Exomes 𝑓: 0.072 (233 hom. 861 hem.)
• Consequence: TAF1 ENST00000715246.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -7.38
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-71366210-A-C is Benign according to our data. Variant chrX-71366210-A-C is described in ClinVar as [Benign]. Clinvar id is 1227807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF1	NM_004606.5	c.-165A>C		upstream_gene_variant		ENST00000423759.6	NP_004597.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF1	ENST00000423759.6	c.-165A>C		upstream_gene_variant		5	NM_004606.5	ENSP00000406549.2

Frequencies

GnomAD3 genomes AF: 0.283 AC: 7377 AN: 26062 Hom.: 656 Cov.: 0

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.0204

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0313

Gnomad EAS AF: 0.00778

Gnomad SAS AF: 0.0639

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.0467

Gnomad NFE AF: 0.0535

Gnomad OTH AF: 0.207

GnomAD4 exome AF: 0.0719 AC: 8309 AN: 115583 Hom.: 233 Cov.: 3 AF XY: 0.0360 AC XY: 861 AN XY: 23909

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

African (AFR) AF: 0.367 AC: 2104 AN: 5735

American (AMR) AF: 0.0791 AC: 362 AN: 4579

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 102 AN: 3084

East Asian (EAS) AF: 0.00805 AC: 51 AN: 6336

South Asian (SAS) AF: 0.100 AC: 829 AN: 8260

European-Finnish (FIN) AF: 0.0556 AC: 655 AN: 11783

Middle Eastern (MID) AF: 0.106 AC: 40 AN: 376

European-Non Finnish (NFE) AF: 0.0525 AC: 3660 AN: 69683

Other (OTH) AF: 0.0880 AC: 506 AN: 5747

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.283 AC: 7397 AN: 26097 Hom.: 656 Cov.: 0 AF XY: 0.225 AC XY: 1239 AN XY: 5497

African (AFR) AF: 0.499 AC: 6493 AN: 13009

American (AMR) AF: 0.157 AC: 297 AN: 1890

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 12 AN: 384

East Asian (EAS) AF: 0.00778 AC: 5 AN: 643

South Asian (SAS) AF: 0.0615 AC: 24 AN: 390

European-Finnish (FIN) AF: 0.0316 AC: 25 AN: 791

Middle Eastern (MID) AF: 0.0526 AC: 5 AN: 95

European-Non Finnish (NFE) AF: 0.0535 AC: 448 AN: 8372

Other (OTH) AF: 0.202 AC: 86 AN: 425

Alfa AF: 0.0703 Hom.: 267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 22, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.67
DANN	Benign	0.19
PhyloP100		-7.4
PromoterAI		-0.078	Neutral

Splicing

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

Other links and lift over

dbSNP: rs7055342; hg19: chrX-70586060;