Genetic Variant TAF1:c.-33C>T (chrX-71366342-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000715246.1(TAF1):c.28C>T(p.Arg10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

TAF1
ENST00000715246.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.11

Publications

0 publications found

Variant links:

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

TAF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08598578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF1	NM_004606.5 link	c.-33C>T		upstream_gene_variant		ENST00000423759.6	NP_004597.3	P21675

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF1	ENST00000423759.6 link	c.-33C>T		upstream_gene_variant		5	NM_004606.5	ENSP00000406549.2		P21675

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1097582

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363182

African (AFR)

AF:

0.00

AC:

AN:

26369

American (AMR)

AF:

0.00

AC:

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54115

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3705

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842031

Other (OTH)

AF:

0.00

AC:

AN:

46049

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 10 of the TAF1 protein (p.Arg10Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TAF1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

.;T;.

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.042

MetaRNN

Benign

0.086

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

-1.1

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.34

N;N;N

REVEL

Benign

0.025

Sift

Uncertain

0.025

D;D;D

Sift4G

Benign

0.087

T;T;T

Polyphen

0.20, 0.31

.;B;B

Vest4

0.14

MutPred

0.35

Gain of catalytic residue at L8 (P = 0.0017);Gain of catalytic residue at L8 (P = 0.0017);Gain of catalytic residue at L8 (P = 0.0017);

MVP

0.14

MPC

0.81

ClinPred

0.32

GERP RS

3.1

PromoterAI

-0.18

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.072

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over