rs139510844

Variant names:

• chrX-71366346-C-T
• rs139510844
• ENST00000373790.9:c.-29C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000373790.9(TAF1):​c.-29C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,207,491 control chromosomes in the GnomAD database, including 16 homozygotes. There are 412 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (10 hom., 185 hem., cov: 20)
  • Exomes 𝑓: 0.00076 (6 hom. 227 hem.)
• Consequence: TAF1 ENST00000373790.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.33
• Publications: 1 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, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked dystonia-parkinsonism

  Inheritance: XL, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031756163).
• BP6: Variant X-71366346-C-T is Benign according to our data. Variant chrX-71366346-C-T is described in ClinVar as Benign. ClinVar VariationId is 289208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00691 (758/109723) while in subpopulation AFR AF = 0.0239 (718/29999). AF 95% confidence interval is 0.0225. There are 10 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000373790.9. 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.-29C>T		upstream_gene	N/A	NP_004597.3
	TAF1	NM_001286074.2		c.-29C>T		upstream_gene	N/A	NP_001273003.2
	TAF1	NM_001440852.1		c.-29C>T		upstream_gene	N/A	NP_001427781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	ENST00000373790.9	TSL:1	c.-29C>T		5_prime_UTR	Exon 1 of 38	ENSP00000362895.5	P21675-13
	TAF1	ENST00000715246.1		c.32C>T	p.Thr11Ile	missense	Exon 1 of 38	ENSP00000520427.1	P21675-2
	TAF1	ENST00000683202.1		c.-29C>T		5_prime_UTR	Exon 1 of 40	ENSP00000507781.1	A0A804HK58

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 758 AN: 109674 Hom.: 10 Cov.: 20

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000949

Gnomad OTH AF: 0.00547

GnomAD2 exomes AF: 0.00202 AC: 371 AN: 183235 AF XY: 0.00125

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000755 AC: 829 AN: 1097768 Hom.: 6 Cov.: 33 AF XY: 0.000625 AC XY: 227 AN XY: 363316

African (AFR) AF: 0.0255 AC: 674 AN: 26384

American (AMR) AF: 0.00116 AC: 41 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30205

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54119

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00106 AC: 4 AN: 3768

European-Non Finnish (NFE) AF: 0.0000404 AC: 34 AN: 842113

Other (OTH) AF: 0.00152 AC: 70 AN: 46057

GnomAD4 genome AF: 0.00691 AC: 758 AN: 109723 Hom.: 10 Cov.: 20 AF XY: 0.00579 AC XY: 185 AN XY: 31947

African (AFR) AF: 0.0239 AC: 718 AN: 29999

American (AMR) AF: 0.00264 AC: 27 AN: 10235

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2625

East Asian (EAS) AF: 0.00 AC: 0 AN: 3472

South Asian (SAS) AF: 0.00 AC: 0 AN: 2557

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000949 AC: 5 AN: 52669

Other (OTH) AF: 0.00540 AC: 8 AN: 1482

Alfa AF: 0.00232 Hom.: 112

Bravo AF: 0.00832

ESP6500AA AF: 0.0256 AC: 98

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00210 AC: 255

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	TAF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.97	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.5
DANN	Benign	0.90
DEOGEN2	Benign	0.067	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.0030
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.082
MPC		0.80
ClinPred		0.00041	T
GERP RS		-5.4
PromoterAI		0.067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.037
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs139510844; hg19: chrX-70586196;