X-71366461-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004606.5(TAF1):c.87C>G(p.Ala29=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 941,126 control chromosomes in the GnomAD database, including 17 homozygotes. There are 1,841 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (3 hom., 100 hem., cov: 15)
  • Exomes 𝑓: 0.0062 (14 hom. 1741 hem.)
• Consequence: TAF1 NM_004606.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.713

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant X-71366461-C-G is Benign according to our data. Variant chrX-71366461-C-G is described in ClinVar as [Benign]. Clinvar id is 695433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71366461-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.713 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00654 (451/68985) while in subpopulation NFE AF= 0.00736 (282/38323). AF 95% confidence interval is 0.00665. There are 3 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 15. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TAF1	NM_004606.5	c.87C>G	p.Ala29=	synonymous_variant	1/38	ENST00000423759.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAF1	ENST00000423759.6	c.87C>G	p.Ala29=	synonymous_variant	1/38	5	NM_004606.5	A2

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 452 AN: 68956 Hom.: 3 Cov.: 15 AF XY: 0.00683 AC XY: 100 AN XY: 14646

Gnomad AFR AF: 0.000806

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.00326

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00738

Gnomad OTH AF: 0.00227

GnomAD3 exomes AF: 0.00443 AC: 709 AN: 160005 Hom.: 2 AF XY: 0.00462 AC XY: 261 AN XY: 56499

Gnomad AFR exome AF: 0.000174

Gnomad AMR exome AF: 0.000489

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000932

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.00557

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00625 AC: 5448 AN: 872141 Hom.: 14 Cov.: 33 AF XY: 0.00623 AC XY: 1741 AN XY: 279345

Gnomad4 AFR exome AF: 0.000763

Gnomad4 AMR exome AF: 0.000912

Gnomad4 ASJ exome AF: 0.00127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.0285

Gnomad4 NFE exome AF: 0.00640

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.00654 AC: 451 AN: 68985 Hom.: 3 Cov.: 15 AF XY: 0.00682 AC XY: 100 AN XY: 14659

Gnomad4 AFR AF: 0.000805

Gnomad4 AMR AF: 0.00326

Gnomad4 ASJ AF: 0.00203

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00412

Gnomad4 FIN AF: 0.0255

Gnomad4 NFE AF: 0.00736

Gnomad4 OTH AF: 0.00225

Alfa AF: 0.00175 Hom.: 9

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

TAF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	12
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28382145; hg19: chrX-70586311;