rs2032476477

Variant names:

• chrX-71366402-T-G
• rs2032476477
• NM_004606.5:c.28T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004606.5(TAF1):​c.28T>G​(p.Ser10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,206,504 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000092 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: TAF1 NM_004606.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13127768).

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.28T>G	p.Ser10Ala	missense	Exon 1 of 38	NP_004597.3
	TAF1	NM_001286074.2		c.28T>G	p.Ser10Ala	missense	Exon 1 of 39	NP_001273003.2
	TAF1	NM_001440852.1		c.28T>G	p.Ser10Ala	missense	Exon 1 of 39	NP_001427781.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAF1	ENST00000423759.6	TSL:5 MANE Select	c.28T>G	p.Ser10Ala	missense	Exon 1 of 38	ENSP00000406549.2	P21675-14
	TAF1	ENST00000373790.9	TSL:1	c.28T>G	p.Ser10Ala	missense	Exon 1 of 38	ENSP00000362895.5	P21675-13
	TAF1	ENST00000683782.1		c.28T>G	p.Ser10Ala	missense	Exon 1 of 39	ENSP00000506996.1	A0A804HIC2

Frequencies

GnomAD3 genomes AF: 0.00000921 AC: 1 AN: 108575 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097929 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363343

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.00 AC: 0 AN: 54127

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4028

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842051

Other (OTH) AF: 0.0000434 AC: 2 AN: 46066

GnomAD4 genome AF: 0.00000921 AC: 1 AN: 108575 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 30965

African (AFR) AF: 0.0000337 AC: 1 AN: 29678

American (AMR) AF: 0.00 AC: 0 AN: 10039

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2616

East Asian (EAS) AF: 0.00 AC: 0 AN: 3410

South Asian (SAS) AF: 0.00 AC: 0 AN: 2477

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5621

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 227

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52403

Other (OTH) AF: 0.00 AC: 0 AN: 1434

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.070
Sift	Benign	0.19	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.41		Loss of glycosylation at S30 (P = 0.0058)
MVP		0.27
MPC		0.64
ClinPred		0.30	T
GERP RS		5.0
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.15
gMVP		0.13
Mutation Taster		=94/6	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: rs2032476477; hg19: chrX-70586252;