X-71366418-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_004606.5(TAF1):c.44C>T(p.Pro15Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000917 in 1,198,959 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000094 ( 0 hom., 0 hem., cov: 20)

Exomes 𝑓: 0.0000091 ( 0 hom. 3 hem. )

Consequence

TAF1
NM_004606.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.49

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in the TAF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 5.486 (above the threshold of 3.09). GenCC associations: The gene is linked to X-linked intellectual disability-global development delay-facial dysmorphism-sacral caudal remnant syndrome, X-linked dystonia-parkinsonism, intellectual disability, X-linked, syndromic 33.

BP4

Computational evidence support a benign effect (MetaRNN=0.2827194).

BP6

Variant X-71366418-C-T is Benign according to our data. Variant chrX-71366418-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 429244.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAF1	NM_004606.5 link	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 38	ENST00000423759.6	NP_004597.3	P21675

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAF1	ENST00000423759.6 link	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 38	5	NM_004606.5	ENSP00000406549.2		P21675

Frequencies

GnomAD3 genomes

AF:

0.00000944

AC:

AN:

105946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29146

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000193

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000915

AC:

AN:

1093013

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

359413

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000944

AC:

AN:

105946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29146

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000193

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.104C>T (p.P35L) alteration is located in exon 1 (coding exon 1) of the TAF1 gene. This alteration results from a C to T substitution at nucleotide position 104, causing the proline (P) at amino acid position 35 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Jan 25, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.067

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.060

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.14, 0.45

.;B;B

Vest4

0.25

MutPred

0.56

Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);

MVP

0.31

MPC

1.4

ClinPred

0.94

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.27

gMVP

0.87

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over